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Microdeletion syndromes (chromosomes 12 to 22)

Microdeletion syndromes (chromosomes 12 to 22)
Literature review current through: Jan 2024.
This topic last updated: Apr 19, 2022.

INTRODUCTION — Chromosome deletions that span at least 5 megabases (Mb) are usually microscopically visible on chromosome-banded karyotypes. Microdeletions, or submicroscopic deletions, are chromosomal deletions that are too small to be detected by light microscopy using conventional cytogenetic methods. Specialized testing is needed to identify these deletions. Microdeletions are typically 1 to 3 Mb long and involve several contiguous genes. The exact size and location of a microdeletion that causes a syndrome may vary, but a specific "critical region" is consistently involved. Most phenotypic effects of these microdeletions are due to haploinsufficiency of a few critical genes or, in some cases, a single gene.

This topic reviews microdeletion syndromes involving chromosomes 12 through 22. Microdeletion syndromes involving chromosomes 1 through 11 are discussed separately, as are microduplication syndromes and congenital abnormalities of the sex chromosomes. Other congenital chromosomal abnormalities, such as trisomies, are also reviewed in detail elsewhere. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microduplication syndromes" and "Sex chromosome abnormalities" and "Congenital cytogenetic abnormalities".)

OVERVIEW OF GENOMIC DISORDERS — Genomic disorders are diseases that result from the loss or gain of chromosomal/deoxyribonucleic acid (DNA) material. The most common and better delineated genomic disorders are divided in two main categories: those resulting from copy number losses (deletion syndromes) and copy number gains (duplication syndromes). (See "Genomic disorders: An overview".)

Copy number variations (CNVs) are submicroscopic genomic differences in the number of copies of one or more sections of DNA that result in DNA gains or losses (figure 1). Some CNVs are pathogenic and cause syndromic disorders with consistent phenotypic features, as are discussed here. Other CNVs are associated with disease susceptibility or resistance, and the same CNV can be associated with several diverse disorders. Still other CNVs are part of normal genetic variation and have no recognized disease association. Contiguous gene syndromes can occur when CNVs affect several adjacent genes. (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Genetic variation'.)

The main mechanism that leads to disease in genomic disorders secondary to deletions and duplications is a change in the copy number of a dose-sensitive gene or genes. Other disease mechanisms include interference with imprinted genes and with regulatory elements outside genes. (See "Genomic disorders: An overview", section on 'Disease mechanisms'.)

Genomic disorders are typically detected by array comparative genomic hybridization (aCGH) (figure 2). Some laboratories confirm gains or losses detected on an array with an independent method, such as fluorescent in situ hybridization (FISH), multiple ligation dependent probe amplification (MLPA), or quantitative polymerase chain reaction (Q-PCR). (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Array comparative genomic hybridization' and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization'.)

13q14 DELETION SYNDROME (RETINOBLASTOMA SYNDROME) — Chromosome 13 deletions can affect many areas of the chromosome. Children with microdeletions affecting the 13q14.11 region have an increased risk of developing retinoblastomas and pineoblastoma (MIM #613884). Intellectual disability and facial dysmorphic features also may occur and depend upon the size of the deletion [1]. Retinoblastoma is caused by mutational inactivation of both alleles of the retinoblastoma (RB1) gene that encodes a tumor suppressor, either through an RB1 germline mutation or with deletion of RB1, as is seen in patients with 13q deletion. Once one of the RB1 alleles is rendered inactive by a deletion encompassing this gene, the risk increases for the remaining RB1 gene to acquire a mutation leading to biallelic inactivation and the origin of a retinoblastoma in retinal tissue. This is known as the Knudson two-hit hypothesis [2]. Children with 13q14 deletion syndrome need regular dilated ophthalmology examinations (done under anesthesia in infants and young children) to screen for retinoblastoma and brain magnetic resonance imaging (MRI) to evaluate for pineoblastoma [3]. The laboratory reporting a deletion on chromosome 13 most often will highlight if RB1 is involved. The evaluation and management of retinoblastoma are discussed in greater detail separately. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis" and "Retinoblastoma: Treatment and outcome" and "Pineal gland masses", section on 'Pineoblastoma'.)

15q11.2 DELETION SYNDROME (BP1-BP2) — The region proximal (more centromeric) to the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) region in chromosome 15 has significant variability in the general population. The deletions and duplications of the region between breakpoints 1 and 2 (BP1-BP2) were considered benign and probably familial variations. However, several reports indicate that deletions in this region may be associated with developmental delay and behavioral abnormalities in some individuals [4-8]. A meta-analysis showed that the intelligence quotient (IQ) in persons carrying the deletion was decreased by 4.3 points [9]. In addition, the frequency for intellectual disability, schizophrenia, and epilepsy was 3.4, 2, and 2.1 percent, respectively. No increase was seen for congenital heart disease and autism in this population.

Many people who carry these deletions are asymptomatic, which can be attributed to nonpenetrance or the need of additional modifiers (genetic and environmental factors). There are four highly conserved genes in this region: NIPA magnesium transporter 1 (NIPA1), NIPA magnesium transporter 2 (NIPA2), cytoplasmic FMR1-interacting protein 1 (CYFIP1), and gamma-tubulin complex protein 5 (GCP5). These genes are not imprinted, and patients with this deletion have normal methylation studies for the 15q11-q13 region. These deletions should not be confused with larger deletions that cause AS or PWS. As shown in many other deletion syndromes on chromosome 15, these rearrangements occur around well-known breakpoints. These breakpoints are areas of the genome that are more prone to recombination.

15q11-13 MATERNAL DELETION SYNDROME (ANGELMAN SYNDROME) — A small interstitial deletion between 15q11 and 15q13 can result in two completely different clinical syndromes depending upon the parental origin of the chromosome. A paternally derived chromosome 15 with this deletion results in Prader-Willi syndrome (PWS), whereas a maternally derived chromosome 15 with a similar deletion is associated with Angelman syndrome (AS). (See '15q11-13 paternal deletion syndrome (Prader-Willi syndrome)' below.)

AS (MIM #105830) is a neurodevelopmental disorder characterized by severe intellectual disability, postnatal microcephaly, and a movement or balance disorder, usually in the form of gait ataxia and/or tremulous movement of limbs [10-12]. AS patients may have any combination of the following behavior characteristics: frequent laughter or smiling; apparent happy demeanor with emotional lability; an easily excitable personality, often with hand flapping movements; hypermotoric behavior; fascination with water; mouthing behaviors; and a short attention span. More than 80 percent of individuals with AS have seizures by the time they reach two years of age. Abnormal electroencephalograms (EEGs) are common with large-amplitude slow-spike waves that can be seen even in the absence of seizures. Sleep is often compromised, with frequent waking and altered sleep cycles. Reported gastrointestinal problems include constipation, gastroesophageal reflux disease, cyclic vomiting, swallowing dysfunction, and eosinophilic esophagitis [13]. Many of these manifestations continue into adolescence and adulthood, and additional features include obesity, scoliosis, anxiety, movement disorders, limited verbal communication, and self-injurious behaviors [14,15].

AS is caused by absence of the maternally inherited copy of the UBE3A gene. UBE3A maps to chromosome 15q11-q13 and encodes E6-associated protein ubiquitin protein ligase 3A [16,17]. UBE3A is subject to genomic imprinting (the differential expression of genetic information depending upon whether the information is inherited from the father or the mother). The maternally inherited copy of the UBE3A gene is functional, and the paternally inherited copy is inactive or silenced. In the normal situation, a functional copy or active of UBE3A from the maternal chromosome prevents AS. (See "Principles of epigenetics" and "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.)

There are four known molecular defects of UBE3A that result in AS:

Classical deletions (approximately 5 to 7 megabases [Mb]) of maternal chromosome 15q11-q13 [18,19].

Paternal uniparental disomy (UPD) [20], where both copies of chromosome 15 are inherited from the father, and no chromosome 15 (including UBE3A) is inherited from the mother.

Imprinting center defects, causing the maternal chromosome to have the methylation and gene expression pattern of a paternal chromosome [21,22].

Point mutations in UBE3A, which produce no functional gene product [23].

Deletions account for over 70 percent of cases of AS. There are a number of breakpoints (BPs; chromosome regions prone to rearrangements) in the 15q11-q13 region known as BP1, BP2, and BP3. Deletions in this region can be subclassified into class I and class II deletions based upon these BPs. Class I deletions are larger and extend from BP1 to BP3, while class II deletions extend from BP2 to BP3 [18]. Patients with class I deletions tend to have greater disease severity when compared with class II patients, with greater difficulties in expressive language, need for more antiseizure medications, and higher incidence of autism spectrum disorders [24].

If AS is suspected, the workup should include methylation studies first, followed by chromosome microarray (array comparative genomic hybridization [aCGH]). If methylation studies are informative for AS, the next step is to determine by microarray if the patient has a class I or class II deletion. If aCGH array is negative, options include UPD studies to determine if the patient has paternal UPD using microsatellite DNA markers or, if available, single nucleotide polymorphisms (SNP) arrays. If a SNP array or composite array is used, it is usually possible to determine whether there is UPD by analysis of the SNP data in the AS/PWS critical region. If UPD studies are negative, imprinting center studies are warranted. Imprinting center abnormalities can be a result of deletions that are familial and inherited. They can also be the result of epimutations (heritable changes in gene expression that do not alter the DNA sequence) that are sporadic and have a low recurrence risk. Sometimes epimutations are postzygotic, resulting in mosaicism [21,24-26]. If the methylation studies are negative and suspicion for AS remains, sequencing studies for UBE3A should be obtained.

Screening and monitoring studies include developmental evaluations and EEG to check for seizures. The EEG is often abnormal; therefore, the author suggests obtaining an EEG after one year of age in all children with AS. Patients should also be evaluated for feeding problems and gastroesophageal reflux. Referrals to physical, occupational, and speech therapy are recommended. Augmentative communication methods may be beneficial. Consider melatonin and/or clonidine to alleviate severe sleep disturbances. Patients with AS who have mild seizures may respond well to the use of clonazepam. There are advances that promise to change the treatment paradigm using antisense oligonucleotide therapies to reactivate the expression of the paternal allele in the imprinted regions of the brain as well as gene therapy using viral vectors [27]. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis" and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Pharmacotherapy for insomnia in adults", section on 'Melatonin' and "Developmental-behavioral surveillance and screening in primary care", section on 'Approach to surveillance'.)

15q11-13 PATERNAL DELETION SYNDROME (PRADER-WILLI SYNDROME) — This deletion is associated with Prader-Willi syndrome (PWS; MIM #176270), which is characterized by hypotonia, poor feeding in infancy with failure to thrive but increased appetite and obesity in children and adults, genital hypoplasia, small hands and feet, and distinctive facial features (eg, almond-shaped eyes, narrowed bifrontal diameter, thin upper lip). The deletion in this case, as opposed to Angelman syndrome (AS), occurs in the paternally derived chromosome 15. Mild intellectual disability occurs in two-thirds of cases. Although the exact gene(s) responsible for PWS are still unknown, two reports have identified possible contributory causes. Truncating mutations in the MAGE family member L2 (MAGEL2) gene that encodes an ubiquitin ligase enhancer involved in endosomal protein recycling were identified in patients with PWS and autism [28]. Although MAGEL2 may contribute to the PWS phenotype, the role of this gene is still unclear [29]. In addition, deletions of the small nucleolar ribonucleic acid (snoRNA) HBII-85 cluster have been reported in PWS [30]. Loss involving the noncoding modifying or guide RNA SNORD116 in the hypothalamus, another nucleolar RNA, is the likely cause for hyperphagia in PWS [31,32]. (See "Prader-Willi syndrome: Management" and "Prader-Willi syndrome: Clinical features and diagnosis".)

15q13.3 DELETION SYNDROME — This 1.5 megabase (Mb) microdeletion (MIM #612001) has a variable phenotype and extends between breakpoints 4 and 5 (BP4 and BP5), which are adjacent and distal to BP1 and BP3, involved in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) deletions [33-37]. The clinical manifestations include mild to severe intellectual disabilities, seizures/epilepsy, behavioral abnormalities, autism, schizophrenia, hypotonia, and visual impairment. The region contains six genes, but cholinergic receptor nicotinic alpha 7 subunit (CHRNA7), a cholinergic receptor gene, appears linked to seizures and the clinical phenotype. Some authors hypothesize that this deletion alone is not sufficient to cause disease and that other abnormalities or modifiers are needed. Several patients whose deletion involves Kruppel-like factor 13 (KLF13), a gene located in the critical region, have congenital heart defects [35].

Screening and monitoring studies include formal developmental and psychologic evaluations and electroencephalogram (EEG). Echocardiography should also be considered. Patients may benefit from physical, occupational, and speech therapies.

15q15.3 DELETION SYNDROME — This is an uncommon contiguous gene deletion syndrome (MIM #611102). The main clinical features associated with this syndrome are sensorineural hearing loss and male infertility due to sperm dysmotility [38]. The disease is autosomal recessive and is caused by haploinsufficiency of cation channel sperm associated 2 (CATSPER2) and stereocilin (STRC), two genes included in the deleted region that are expressed in the sperm and inner ear, respectively. Males who inherit two CATSPER2-STRC deletions are infertile and deaf [39]. Females who inherit two CATSPER2-STRC deletions are deaf.

Hearing evaluations should be performed in patients with this deletion. Males should also be tested for infertility.

15q24 DELETION SYNDROME — This rare deletion disorder ranges from 1.7 to 3.9 megabases (Mb) in size. The core cognitive features of the 15q24 microdeletion syndrome, including developmental delays and severe speech problems, are largely due to deletion of genes in a critical region that encompasses 1.1 Mb [40].

The majority of breakpoints lie within segmental duplication (SD) blocks. The region is surrounded by multiple locus control regions (LCRs) that control chromatin structure and amplify expression of linked genes.

The syndrome is characterized by mild to moderate intellectual disability, growth retardation, microcephaly, digital abnormalities, hypospadias, and connective tissue abnormalities (loose joints; MIM #613406) [41-43]. Patients have distinctive dysmorphic features including a receding hairline, hypertelorism, epicanthal folds, broad inner aspect of the eyebrows, downslanting palpebral fissures, broad nasal bridge, long smooth philtrum, thin upper lip, and a full lower lip. Skeletal findings include delayed bone age, brachydactyly, and broad phalanges with distal hypoplasia. Genital anomalies include hypospadias, micropenis, and a small scrotum. Congenital diaphragmatic hernia has been frequently reported in this deletion [44]. Other, less frequent anomalies can include intestinal atresia, imperforate anus, hearing loss, growth hormone deficiency, cardiovascular anomalies, and meningomyelocele [45].

Cytochrome P450 family 11 subfamily A member 1 (CYP11A1) maps to the region and encodes cytochrome P450 side-chain cleavage enzyme (P450scc), which converts cholesterol to pregnenolone, the initial and rate-limiting step in the production of progesterone. Deletion of this gene may be responsible for the genital abnormalities in males (complete absence of this gene causes sex reversal in males and congenital adrenal insufficiency). Other deleted genes include a number of enzymes involved in glycosylation (loss of both copies is usually required to exhibit symptoms; thus, this deletion may uncover recessive phenotypes). Other genes potentially responsible for this phenotype includes complexin 3 (CPLX3), a regulator of neurotransmitter release that is expressed in the brain and eye, and semaphorin 7A (SEMA7A), a gene that mediates peripheral and central axon growth required during neuronal development [46].

Heterozygous pathogenic variants leading to haploinsufficiency of SIN3 transcription regulator (SIN3), a gene located in this region, has been reported in association with Witteveen-Kolk syndrome. This syndrome presents with developmental and speech delays, autistic features, and seizures. These patients present with a broad forehead, long face, downslanting palpebral fissures, flat or depressed nasal bridge, large fleshy ears, long and smooth philtrum, small mouth, and pointed chin. In addition, other features include microcephaly, hypermobile joints, short stature, and small hands and feet. Brain anomalies include migration defects, enlarged ventricles, and abnormalities of the corpus callosum. Many of these features overlap with those with 15q24 deletions [47].

Screening and monitoring studies include formal developmental evaluation and skeletal survey to uncover skeletal anomalies. Males may need endocrine evaluations, and other imaging studies should be considered to evaluate for diaphragmatic hernias. Patients may benefit from physical, occupational, and speech therapies. Brain imaging, echocardiogram, hearing evaluation, and ophthalmologic evaluation are other screenings that may be performed at the time of diagnosis. Growth and feeding should be closely monitored.

16p13.3 DELETION SYNDROME (RUBINSTEIN-TAYBI SYNDROME) — A submicroscopic deletion that includes the cAMP response element-binding protein (CREB) binding protein gene, CREBBP or CBP, located on chromosome 16 at p13.3, has been identified in approximately 10 percent of individuals with Rubinstein-Taybi syndrome (RTS; MIM #180849) [48,49]. This clinical entity is characterized by prenatal and postnatal growth restriction, microcephaly, dysmorphic features, broad thumbs and toes, and intellectual disability [50-53]. Facial features include highly arched eyebrows, long eyelashes, beaked nose with prominent septum extending below nares, downslanting palpebral fissures, high-arched palate, and micrognathia. The thumbs are broad and radially deviated, and the toes are also quite broad and internally deviated. The incisors may have talon cusps. Hirsutism is commonly seen. Congenital heart disease is seen in one-third of patients. Eye abnormalities may include glaucoma, cataracts, and strabismus.

Mutation of the CBP gene has been detected in approximately 40 percent of affected individuals with RTS. Mutations in another gene, E1A binding protein p300 (EP300), account for a small number of cases [54,55]. Other yet unknown genes may also be responsible for this disorder because approximately 50 percent of individuals with clinical features consistent with RTS do not have a detectable deletion or mutation in CBP or EP300.

Screening and monitoring studies include developmental and ophthalmologic evaluations. An echocardiogram should be performed to evaluate for congenital heart disease.

16p13.11 DELETION SYNDROME — A recurrent 1.65 megabases (Mb) deletion of this region is associated with intellectual disabilities and multiple congenital anomalies. Clinical findings include developmental delay (motor, speech, and language delays), as well as behavioral/psychiatric problems. Patients with this deletion also have microcephaly, short stature, and epilepsy [56-58]. Mild dysmorphic features are present but without a specific pattern. Polymicrogyria was reported in one patient. This deletion is reported as one of the most prevalent deletions predisposing patients to idiopathic epilepsy [57,59].

Screening studies include formal developmental evaluations, electroencephalogram (EEG), and brain magnetic resonance imaging (MRI) studies (to look for central nervous system [CNS] anomalies, such as polymicrogyria and other neuronal migration defects) in the presence of microcephaly.

16p12.2 DELETION SYNDROME — This deletion has variable clinical findings and is not a recognizable syndrome given the degree of variability. It encompasses 520 kb in the area comprised by coordinates 21,948,445-22,430,805 in the reference genome GRCHc37/hG19. The most common features associated with this deletion are developmental delay/intellectual disability, speech delays, epilepsy, autism, psychiatric disorders (depression, schizophrenia, mood disorders, alcoholism), mild dysmorphic features with no specific pattern, sleep disturbances, and congenital heart defects (hypoplastic left heart, ventricular septal defect [VSD], bicuspid aortic valve, aortic stenosis, patent foramen ovale [PFO], patent ductus arteriosus [PDA]). It is not uncommon to find a family history of learning disorders [60].

Screening includes comprehensive developmental evaluations and echocardiogram. Referral for physical, occupational, and speech therapy is recommended. Parental testing as well as other relatives at risk for the 16p12.2 deletion is also recommended.

16p11.2 DELETION SYNDROME — This deletion in 16p11.2 spans almost 600 kb at position 29.5 to 30.1 megabases (Mb) [61]. It is recurrent in size due to flanking segments that mediate these rearrangements. Clinical findings include variable levels of intellectual disability with a high incidence of language delay, expressive more so than receptive [44,62-66]. It is one of the most common deletions predisposing to neurodevelopmental and neuropsychiatric problems and is considered one of the most common recurrent genomic disorders associated with autism spectrum disorders [65]. Some studies have shown that up to 55 percent of patients with this deletion met criteria for autism or autism spectrum disorders, and the frequency of this microdeletion is approximately 0.6 percent in patients with autism [67,68]. Functional magnetic resonance imaging (fMRI) mapping studies have revealed that carriers of this deletion have an impairment in prefrontal brain connectivity leading to weaker frontoparietal region coupling that ultimately results in sociocognitive impairments [69]. The deletion interval includes the MAPK3 gene that encodes mitogen-activated protein kinase 3 (also called extracellular signal-regulated kinase 1 [ERK1]). Mutations that regulate ERK pathways have been implicated in neurocognitive disorders and autism [70].

Other data indicate that this deletion may contribute to psychiatric disorders including attention deficit hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, and panic disorder [67,71]. Some patients with this deletion have been diagnosed with cervicothoracic syringomyelia [72] and are also at higher than average risk for seizures and/or electroencephalogram (EEG) abnormalities. There are several reported patients with a smaller deletion, approximately 200 kb, distal to the classical deletion (coordinates 29.7 to 29.9 Mb) who present with class 2 obesity [73,74]. Thus, obesity can be part of this deletion phenotype.

Formal developmental, neuropsychiatric, and autism evaluations may be required. Spine MRI should be considered since syringomyelia may be asymptomatic. Other screening and monitoring studies include speech and hearing evaluation, EEG, and monitoring of weight gain and overall growth. (See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis" and "Autism spectrum disorder in children and adolescents: Screening tools" and "Developmental-behavioral surveillance and screening in primary care", section on 'Approach to surveillance'.)

17p13.3 DELETION SYNDROMES — There are several deletions in the 17p13.3 region, and the clinical manifestations depend upon the size and genes involved. Larger deletions of the distal short arm of chromosome 17 are responsible for Miller-Dieker syndrome (MDS). These deletions involve platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1; the lissencephaly gene formerly known as LIS1). There are more distal deletions that encompass tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHAE; and do not involve PAFAH1B1) that have a distinct clinical phenotype [75].

17p13.3 deletion including PAFAH1B1 (Miller-Dieker syndrome) — MDS (MIM #247200) is a contiguous gene deletion syndrome that is characterized by lissencephaly, growth restriction, and dysmorphic features [76-80]. Haploinsufficiency of LIS1 (now called PAFAH1B1) due to point mutations or deletions is causative of lissencephaly, a generalized agyria-pachygyria brain malformation that results from an arrest of neuronal migration at 9 to 13 weeks gestation [81,82]. (See "Microcephaly in infants and children: Etiology and evaluation", section on 'Neuroanatomic abnormalities'.)

The craniofacial clinical features seen in MDS include a prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw [83]. The clinical course of these patients is marked by failure to thrive, severe psychomotor retardation, opisthotonos, seizures, and death early in life, with very few children reaching 10 years of age. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis", section on 'CNS malformations' and "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Lissencephaly'.)

Some patients have smaller deletions or mutations involving PAFAH1B1 that are associated with isolated lissencephaly (LIS type 1 or classic lissencephaly; MIM #607432) [84,85].

Patients should undergo formal developmental evaluation. Brain magnetic resonance imaging (MRI) studies are recommended to delineate the degree of lissencephaly and structural central nervous system (CNS) abnormalities. Neurology evaluation and electroencephalogram (EEG) are recommended for evaluation and management of seizures. Swallowing evaluations are usually necessary, and patients may need an intragastric or transpyloric feeding tube. (See "Seizures and epilepsy in children: Classification, etiology, and clinical features", section on 'Neurodevelopmental lesions' and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Overview of enteral nutrition in infants and children" and "Enteral feeding: Gastric versus post-pyloric".)

17p13.3 deletion including YWHAE — A series of patients with deletions including tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHAE), but not PAFAH1B1, presented with significant growth restriction, cognitive impairment, shared craniofacial features, and variable structural abnormalities of the brain, but no lissencephaly [86]. One patient in this group did not have growth restriction. CRK proto-oncogene, adaptor protein (CRK) appears to be the gene responsible for growth restriction [87]. YWHAE, a gene involved in the region that encodes tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon, is believed responsible for the brain findings.

Features of this microdeletion syndrome include prenatal and postnatal growth retardation, macrocephaly, and dysmorphic features including prominent forehead, downslanting palpebral fissures, epicanthal folds, broad nasal root, low-set ears, cleft palate, and eye abnormalities. Seizures have been reported. MRI studies show microcysts in the white matter and corpus callosum, ventricular dilatation, enlargement of subarachnoid spaces, and Chiari type I malformation [75,83,87].

Patients should undergo formal developmental evaluation. Brain MRI studies are recommended to determine the presence of structural CNS abnormalities. Neurology evaluation with EEG and ophthalmologic evaluation are also recommended.

17p11.2 DELETION SYNDROME (HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSY) — Hereditary neuropathy with liability to pressure palsy (HNPP; MIM #162500) is an autosomal entity characterized by recurrent mononeuropathy, typically associated with minor compression or trauma [88]. It is associated with deletions in 17p11.2 involving the peripheral myelin protein 22 (PMP22) gene. Population studies using chromosome microarrays suggest that many individuals harboring this deletion remain undiagnosed. Use of protective gear when practicing sports, protective pads at pressure points, and avoidance of repetitive movements or activities may prevent nerve trauma. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'Hereditary neuropathy with liability to pressure palsy'.)

17p11.2 DELETION SYNDROME (SMITH-MAGENIS SYNDROME) — This deletion of chromosome 17p11.2 (image 1) involves the retinoic acid-induced 1 (RAI1) gene that is suspected to be a transcriptional regulator. Both microdeletions and mutations of RAI1 can cause Smith-Magenis syndrome (SMS; MIM #182290) [89-94]. The circadian defect seen in this disorder is due to disruption of transcription of the circadian locomotor output cycles kaput (CLOCK) gene [95].

The syndrome is characterized by brachycephaly, midface hypoplasia, prognathism, hoarse voice, speech delay with or without hearing loss, psychomotor and growth retardation, cutaneous features, and behavior problems [96-99]. Feeding problems are seen in infants, along with hypotonia and sometimes lethargy. Patients have mild to moderate intellectual disability and autism spectrum disorder. Sleep problems are often significant and include difficulty falling asleep, shortened sleep cycles, frequent and prolonged nocturnal awakenings (altered rapid eye movement [REM] sleep), excessive daytime sleepiness, daytime napping, snoring, and bedwetting [100]. Sleep problems appear to be due to an inversion of melatonin secretion. Behavioral abnormalities include head banging, hand and wrist biting, onychotillomania (pulling own nails), excessive nose picking, and polyembolokoilomania (inserting objects in body orifices) [97]. Self-hugging is also a typical behavior. Poor sleep can contribute to behavior problems. Electroencephalograms (EEGs) are frequently abnormal but are not associated with overt seizures. (See "Assessment of sleep disorders in children".)

Some patients display neurologic signs, such as decreased or absent deep tendon reflexes, pes planus or pes cavus, decreased sensitivity to pain, and decreased leg muscle mass suggestive of peripheral neuropathy [101]. The deletion in these patients involves the peripheral myelin protein 22 (PMP22) gene. Other common problems include hearing loss and, in some cases, hyperacusis, short stature, scoliosis, velopharyngeal insufficiency, and ocular abnormalities (iris anomalies, microcornea). (See '17p11.2 deletion syndrome (Hereditary neuropathy with liability to pressure palsy)' above.)

Elevated cholesterol and triglycerides are common. Hypothyroidism is reported in up to half of these patients [102].

Screening laboratory studies include thyroid function tests and lipid panel. Patients should undergo a formal developmental evaluation. Swallowing evaluation is indicated in infants with feeding problems. Ophthalmologic evaluations are important, as well as hearing evaluations. Cardiac evaluations including echocardiography are recommended to rule out structural anomalies. Neuroimaging, sleep, and EEG studies are strongly recommended. In patients with large deletions, nerve conduction velocity studies are recommended to evaluate for hereditary neuropathy with liability to pressure palsy (HNPP).

Patients may benefit from occupational, physical, and speech therapies. Management of sleep and behavioral abnormalities may require psychotropic medications. Additional options that include medications that counteract the inversion of melatonin secretion are discussed in greater detail separately. (See "Medical disorders resulting in problem sleeplessness in children", section on 'Melatonin'.)

17q12 DELETION SYNDROME — This deletion is recurrent in size due to flanking segments that mediate these rearrangements and spans approximately 1.5 megabases (Mb) [103,104]. The critical gene in this region is the hepatocyte nuclear factor-1-beta (HNF1B), also called transcription factor 2 (TCF2) [105]. Clinical findings include congenital kidney anomalies (multicystic kidney disease) and maturity-onset diabetes of the young type 5 (MODY5; MIM #137920). Cognitive impairment and central nervous system (CNS) abnormalities may be part of the clinical spectrum [104]. This deletion confers a higher risk for autism and schizophrenia [106]. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Hepatocyte nuclear factor-1-alpha' and "Kidney cystic diseases in children".)

The reciprocal duplication appears to be associated with an increased risk for epilepsy, but the extent of the clinical consequences is not yet clear.

Screening studies include kidney ultrasound and brain magnetic resonance imaging (MRI). Referral to an endocrinologist is recommended for management of diabetes. (See "Management of type 2 diabetes mellitus in children and adolescents".)

17q21.31 DELETION SYNDROME — This deletion involves the gene encoding microtubule associated protein tau (MAPT) and is associated with a common inversion polymorphism, known as the H2 inversion, in at least one of the parents. This inversion appears to mediate aberrant recombination events leading to the deletion. It was originally thought that the MAPT gene encoding MAPT was the gene causative for this disorder [107,108]. However, it was subsequently determined that this disorder is due to haploinsufficiency of the KAT8 regulatory nonspecific lethal [NSL] complex subunit 1 (KANSL1) gene instead [109,110]. KANSL1 is a regulator of a chromatin modifier, KAT8, that effects gene expression. As such, this condition is now known as KANSL1-related intellectual disability syndrome [111].

Clinically, this microdeletion is associated with mild to severe intellectual disability, hypotonia, and characteristic facies [107,108,112-115]. The hypotonia is also associated with poor sucking and feeding difficulties early on in infancy. Craniofacial features in these patients include a long face, large ears, and tubular or pear-shaped nose with a bulbous nasal tip. Other features include seizures in over half of cases, cardiac defects (septal defects), cryptorchidism in almost 80 percent of males, and skeletal anomalies (slender lower limbs, hip dislocation, feet deformities, and scoliosis). Patients typically have a friendly disposition, sometimes with frequent laughing that is reminiscent of Angelman syndrome (AS). Attention span problems and hyperactivity are also reported.

Management of these patients includes developmental evaluations, an echocardiogram to examine for cardiac defects, brain magnetic resonance imaging (MRI), and referral to neurology for electroencephalogram (EEG) and management of seizures, if present. Physical, occupational, and speech therapies are helpful, particularly for issues with hypotonia and feeding. Patients may also benefit from augmentative communication methods.

18p DELETION SYNDROME — The estimated frequency of 18p deletion syndrome is 1 in 50,000 liveborn infants, with more females than males affected [116]. Deletions can range in size from the whole short arm of chromosome 18 to microdeletions. The terminal deletion occurs de novo in approximately two-thirds of cases. The remaining cases are due to a de novo unbalanced translocation with loss of the 18p or malsegregation of parental chromosome rearrangement (balanced translocation or inversion) or a ring chromosome 18 [117]. Familial transmission of the del(18p) syndrome has been reported. The 18p deletion can usually be diagnosed by conventional cytogenetic analysis, but is now often detected by array comparative genomic hybridization (aCGH) testing.

The phenotype is variable, depending upon the size and location of the deleted region. Major clinical features may include hypotonia, short stature, microcephaly and brachycephaly, round face with short philtrum, palpebral ptosis, large ears with detached pinnae, downturned corners of the mouth, and mild to moderate cognitive impairment with speech delay [116,118,119]. Approximately 10 to 15 percent of cases present with holoprosencephaly (HP) [116,120]. Some patients with HP may present with bilateral cleft lip and palate, while others may display a single maxillary central incisor, a subtle manifestation of HP. Mutations in the TGFB-induced factor (TGIF) gene that is located in 18p11.3 are associated with HP, but not all patients with deletion of TGIF have HP, indicating a more complex interaction. Approximately 10 percent of cases may present with congenital heart defects [121]. Severe keratosis pilaris and ulerythema ophryogenes [122], autoimmune disease [119,123], and antibody deficiencies [124] have also been reported.

Patients with this deletion should have a brain magnetic resonance imaging (MRI) to assess for HP and other central nervous system (CNS) abnormalities. An echocardiogram should be considered if clinically indicated. Other recommended clinical interventions include physical therapy for hypotonia and speech therapy.

20p11 DELETION SYNDROME (ALAGILLE SYNDROME) — Alagille syndrome (MIM #118450) is mostly due to mutations in Jagged-1 (JAG1), but some patients have a microdeletion that includes this entire gene [125]. This syndrome is characterized by paucity of interlobular bile ducts, chronic cholestasis, cardiac anomalies, butterfly vertebrae, posterior embryotoxon of the eye, and dysmorphic facies. Alagille syndrome is covered in greater detail separately. (See "Inherited disorders associated with conjugated hyperbilirubinemia", section on 'Alagille syndrome'.)

22q11.2 DELETION SYNDROMES (DiGEORGE SYNDROME/VELOCARDIOFACIAL SYNDROME) — This region in chromosome 22 is surrounded by low-copy repeats known as LCR22-1 through 6. The classic velocardiofacial syndrome (VCFS)/DiGeorge deletion is approximately 3 megabases (Mb) and includes the T-box transcription factor 1 (TBX1) gene between LCR22-1 and LCR22-3 [126].

Approximately 80 to 90 percent of patients with DiGeorge syndrome (MIM #188400) have microdeletions involving chromosome 22q11 (ie, 22q11.21-q11.23). This syndrome is characterized by abnormalities in the development of the third and fourth branchial arches, resulting in hypoplasia of the thymus and/or parathyroid gland, conotruncal cardiac defects, and facial dysmorphism. Clinical manifestations may include neonatal hypocalcemia and susceptibility to infection, as well as a predisposition to autoimmune diseases later in life. Mild to moderate learning difficulties are common.

VCFS has some overlapping features with DiGeorge syndrome, such as conotruncal cardiac defects and facial abnormalities, and is also caused by interstitial deletions of 22q11. Molecular deletions are detected in 90 percent of individuals, while cytogenetically visible deletions are observed in approximately 15 to 30 percent of cases.

The clinical manifestations, diagnosis, and treatment of this disorder are discussed separately. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis".)

22q11.2 DISTAL DELETION SYNDROME — A number of deletions occur distally to the classic velocardiofacial syndrome (VCFS)/DiGeorge 22q11.2 deletion (MIM #611867) [127-129], including one between LCR22-4 and LCR22-6 of approximately 2.1 megabases (Mb) and another one between LCR22-5 and LCR22-6 spanning 1.4 Mb. All patients with these deletions presented with characteristic dysmorphic features, history of prematurity, prenatal and postnatal growth restriction that may correct in childhood, developmental delay/learning disabilities, and mild skeletal abnormalities. The craniofacial features include arched eyebrows, deep-set eyes, a smooth philtrum, a thin upper lip, hypoplastic alae nasi, and a small, pointed chin. A few patients have cardiovascular malformations (truncus arteriosus, bicuspid aortic valve).

Management of these patients includes developmental evaluations, an echocardiogram to examine for cardiac defects, and occupational and speech therapies.

22q13.3 DELETION SYNDROME (PHELAN-MCDERMID SYNDROME) — Deletions of distal 22q13.3 (MIM #606232) are associated with generalized hypotonia, global developmental delay, severe speech delay, and normal to advanced growth [130-134]. The deletion encompasses the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene that is responsible for the neurologic findings [135-137]. This deletion is also associated with severe expressive language delays and autism.

Formal developmental and autism evaluations are recommended. Management includes occupational and speech therapies. Patients may benefit from augmentative communication methods. (See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis" and "Autism spectrum disorder in children and adolescents: Screening tools" and "Developmental-behavioral surveillance and screening in primary care", section on 'Approach to surveillance'.)

SUMMARY

Microdeletions – Microdeletions, or submicroscopic deletions, are chromosomal deletions that are too small to be detected by light microscopy using conventional cytogenetics methods. (See 'Introduction' above.)

15q11-13 deletion syndromes – 15q11-13 deletion syndromes are some of the most common microdeletions. A paternally derived chromosome 15 with this deletion results in Prader-Willi syndrome (PWS; MIM #176270), whereas a maternally derived chromosome 15 with a similar deletion is associated with Angelman syndrome (AS; MIM #105830). PWS is characterized by hypotonia; poor feeding in infancy with failure to thrive but increased appetite and obesity in children and adults; genital hypoplasia; small hands and feet; and distinctive facial features. AS is a neurodevelopmental disorder characterized by severe to profound intellectual disability, postnatal microcephaly, and a movement or balance disorder, usually in the form of gait ataxia and/or tremulous movement of limbs. Patients also often have seizures and characteristic behaviors. (See '15q11-13 maternal deletion syndrome (Angelman syndrome)' above and '15q11-13 paternal deletion syndrome (Prader-Willi syndrome)' above.)

22q11.2 deletion syndromes (DiGeorge syndrome and velocardiofacial syndrome) – More than 90 percent of patients with DiGeorge syndrome (MIM #188400) have microdeletions involving chromosome 22q11.2. This syndrome is characterized by abnormalities in the development of the third and fourth branchial arches, resulting in hypoplasia of the thymus and/or parathyroid gland, conotruncal cardiac defects, and facial dysmorphism. Clinical manifestations may include neonatal hypocalcemia, susceptibility to infection, mild to moderate learning difficulties, as well as a predisposition to autoimmune diseases later in life.

Velocardiofacial syndrome (VCFS) has some overlapping features with DiGeorge syndrome, such as conotruncal cardiac defects and facial abnormalities, and is also caused by interstitial deletions of 22q11. (See '22q11.2 deletion syndromes (DiGeorge syndrome/velocardiofacial syndrome)' above.)

Genomic disorders – Genomic disorders are diseases that result from the loss or gain of chromosomal/DNA material. The most common and better delineated genomic disorders are divided in two main categories: those resulting from copy number losses (deletion syndromes) and copy number gains (duplication syndromes). (See 'Overview of genomic disorders' above.)

16p11.2 deletion syndrome – 16p11.2 deletion syndrome is one of the most common recurrent genomic disorders associated with neurodevelopmental, neuropsychiatric, and autism spectrum disorders. It shows incomplete penetrance and variable expressivity. Clinical findings include variable levels of intellectual disability with a high incidence of language delay, expressive more so than receptive. (See '16p11.2 deletion syndrome' above.)

  1. Mitter D, Ullmann R, Muradyan A, et al. Genotype-phenotype correlations in patients with retinoblastoma and interstitial 13q deletions. Eur J Hum Genet 2011; 19:947.
  2. Mendoza PR, Grossniklaus HE. The Biology of Retinoblastoma. Prog Mol Biol Transl Sci 2015; 134:503.
  3. GeneReviews: Retinoblastoma. http://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/books/NBK1452/ (Accessed on April 21, 2014).
  4. Burnside RD, Pasion R, Mikhail FM, et al. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum Genet 2011; 130:517.
  5. Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, et al. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet 2009; 52:108.
  6. Murthy SK, Nygren AO, El Shakankiry HM, et al. Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment. Cytogenet Genome Res 2007; 116:135.
  7. Sempere Pérez A, Manchón Trives I, Palazón Azorín I, et al. [15Q11.2 (BP1-BP2) microdeletion, a new syndrome with variable expressivity]. An Pediatr (Barc) 2011; 75:58.
  8. Cox DM, Butler MG. The 15q11.2 BP1-BP2 microdeletion syndrome: a review. Int J Mol Sci 2015; 16:4068.
  9. Jønch AE, Douard E, Moreau C, et al. Estimating the effect size of the 15Q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice. J Med Genet 2019; 56:701.
  10. Williams CA, Angelman H, Clayton-Smith J, et al. Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation. Am J Med Genet 1995; 56:237.
  11. Williams CA, Beaudet AL, Clayton-Smith J, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A 2006; 140:413.
  12. GeneReviews: Angelman Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK1144/ (Accessed on January 18, 2012).
  13. Glassman LW, Grocott OR, Kunz PA, et al. Prevalence of gastrointestinal symptoms in Angelman syndrome. Am J Med Genet A 2017; 173:2703.
  14. Larson AM, Shinnick JE, Shaaya EA, et al. Angelman syndrome in adulthood. Am J Med Genet A 2015; 167A:331.
  15. Prasad A, Grocott O, Parkin K, et al. Angelman syndrome in adolescence and adulthood: A retrospective chart review of 53 cases. Am J Med Genet A 2018; 176:1327.
  16. Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 1997; 15:70.
  17. Matsuura T, Sutcliffe JS, Fang P, et al. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet 1997; 15:74.
  18. Sahoo T, Peters SU, Madduri NS, et al. Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations. J Med Genet 2006; 43:512.
  19. Saitoh S, Buiting K, Cassidy SB, et al. Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome patients with an imprinting mutation. Am J Med Genet 1997; 68:195.
  20. Malcolm S, Clayton-Smith J, Nichols M, et al. Uniparental paternal disomy in Angelman's syndrome. Lancet 1991; 337:694.
  21. Buiting K, Gross S, Lich C, et al. Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet 2003; 72:571.
  22. Buiting K, Lich C, Cottrell S, et al. A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp. Hum Genet 1999; 105:665.
  23. Abaied L, Trabelsi M, Chaabouni M, et al. A novel UBE3A truncating mutation in large Tunisian Angelman syndrome pedigree. Am J Med Genet A 2010; 152A:141.
  24. Peters SU, Beaudet AL, Madduri N, Bacino CA. Autism in Angelman syndrome: implications for autism research. Clin Genet 2004; 66:530.
  25. Horsthemke B, Buiting K. Imprinting defects on human chromosome 15. Cytogenet Genome Res 2006; 113:292.
  26. Horsthemke B, Dittrich B, Buiting K. Imprinting mutations on human chromosome 15. Hum Mutat 1997; 10:329.
  27. Beaudet AL, Meng L. Gene-targeting pharmaceuticals for single-gene disorders. Hum Mol Genet 2016; 25:R18.
  28. Schaaf CP, Gonzalez-Garay ML, Xia F, et al. Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism. Nat Genet 2013; 45:1405.
  29. Buiting K, Di Donato N, Beygo J, et al. Clinical phenotypes of MAGEL2 mutations and deletions. Orphanet J Rare Dis 2014; 9:40.
  30. Sahoo T, del Gaudio D, German JR, et al. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet 2008; 40:719.
  31. Rodriguez JA, Zigman JM. Hypothalamic loss of Snord116 and Prader-Willi syndrome hyperphagia: the buck stops here? J Clin Invest 2018; 128:900.
  32. Polex-Wolf J, Lam BY, Larder R, et al. Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome. J Clin Invest 2018; 128:960.
  33. Miller DT, Shen Y, Weiss LA, et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 2009; 46:242.
  34. Sharp AJ, Mefford HC, Li K, et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 2008; 40:322.
  35. van Bon BW, Mefford HC, Menten B, et al. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 2009; 46:511.
  36. GeneReviews: 15q13.3 Microdeletion. http://www.ncbi.nlm.nih.gov/books/NBK50780/ (Accessed on January 18, 2012).
  37. Prasun P, Hankerd M, Kristofice M, et al. Compound heterozygous microdeletion of chromosome 15q13.3 region in a child with hypotonia, impaired vision, and global developmental delay. Am J Med Genet A 2014; 164A:1815.
  38. Hildebrand MS, Avenarius MR, Smith RJH. CATSPER-related male infertility. In: GeneReviews, Pagon RA, Bird TD, Dolan CR, Stephens K (Eds), Seattle (WA), University of Washington, Seattle; 1993-2009 Dec 03. PMID: 20301780.
  39. GeneReviews: CATSPER-Related Male Infertility. http://www.ncbi.nlm.nih.gov/books/NBK22925/ (Accessed on January 18, 2012).
  40. Mefford HC, Rosenfeld JA, Shur N, et al. Further clinical and molecular delineation of the 15q24 microdeletion syndrome. J Med Genet 2012; 49:110.
  41. Klopocki E, Graul-Neumann LM, Grieben U, et al. A further case of the recurrent 15q24 microdeletion syndrome, detected by array CGH. Eur J Pediatr 2008; 167:903.
  42. McInnes LA, Nakamine A, Pilorge M, et al. A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region. Mol Autism 2010; 1:5.
  43. Sharp AJ, Selzer RR, Veltman JA, et al. Characterization of a recurrent 15q24 microdeletion syndrome. Hum Mol Genet 2007; 16:567.
  44. Van Esch H, Backx L, Pijkels E, Fryns JP. Congenital diaphragmatic hernia is part of the new 15q24 microdeletion syndrome. Eur J Med Genet 2009; 52:153.
  45. Magoulas PL, El-Hattab AW. Chromosome 15q24 microdeletion syndrome. Orphanet J Rare Dis 2012; 7:2.
  46. Zhang Y, Liu X, Gao H, et al. Molecular and phenotypic characteristics of 15q24 microdeletion in pediatric patients with developmental disorders. Mol Cytogenet 2021; 14:57.
  47. Witteveen JS, Willemsen MH, Dombroski TC, et al. Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity. Nat Genet 2016; 48:877.
  48. Punnett HH, Zakai EH. Old syndromes and new cytogenetics. Dev Med Child Neurol 1990; 32:824.
  49. Breuning MH, Dauwerse HG, Fugazza G, et al. Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3. Am J Hum Genet 1993; 52:249.
  50. RUBINSTEIN JH, TAYBI H. Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. Am J Dis Child 1963; 105:588.
  51. Hennekam RC. Rubinstein-Taybi syndrome. Eur J Hum Genet 2006; 14:981.
  52. Hennekam RC, Lommen EJ, Strengers JL, et al. Rubinstein-Taybi syndrome in a mother and son. Eur J Pediatr 1989; 148:439.
  53. GeneReviews: Rubinstein-Taybi Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK1526/ (Accessed on January 18, 2012).
  54. Roelfsema JH, White SJ, Ariyürek Y, et al. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet 2005; 76:572.
  55. Tsai AC, Dossett CJ, Walton CS, et al. Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein-Taybi syndrome detected by aCGH. Eur J Hum Genet 2011; 19:43.
  56. Hannes FD, Sharp AJ, Mefford HC, et al. Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 2009; 46:223.
  57. Heinzen EL, Radtke RA, Urban TJ, et al. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet 2010; 86:707.
  58. Nagamani SC, Erez A, Bader P, et al. Phenotypic manifestations of copy number variation in chromosome 16p13.11. Eur J Hum Genet 2011; 19:280.
  59. de Kovel CG, Trucks H, Helbig I, et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010; 133:23.
  60. Girirajan S, Pizzo L, Moeschler J, Rosenfeld J. 16p12.2 recurrent deletion. In: GeneReviews [Internet], Adam MP, Ardinger HH, Pagon RA, et al (Eds), University of Washington, Seattle 2018.
  61. Human Genome Browser (HG18). http://genome.ucsc.edu/cgi-bin/hgGateway?db=hg18 (Accessed on April 09, 2014).
  62. Ballif BC, Hornor SA, Jenkins E, et al. Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nat Genet 2007; 39:1071.
  63. Fernandez BA, Roberts W, Chung B, et al. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. J Med Genet 2010; 47:195.
  64. Hanson E, Nasir RH, Fong A, et al. Cognitive and behavioral characterization of 16p11.2 deletion syndrome. J Dev Behav Pediatr 2010; 31:649.
  65. Kumar RA, KaraMohamed S, Sudi J, et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 2008; 17:628.
  66. GeneReviews: 16p11.2 Microdeletion. http://www.ncbi.nlm.nih.gov/books/NBK11167/ (Accessed on January 18, 2012).
  67. Weiss LA, Shen Y, Korn JM, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358:667.
  68. Kumar RA, Marshall CR, Badner JA, et al. Association and mutation analyses of 16p11.2 autism candidate genes. PLoS One 2009; 4:e4582.
  69. Bertero A, Liska A, Pagani M, et al. Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human. Brain 2018; 141:2055.
  70. Pucilowska J, Vithayathil J, Tavares EJ, et al. The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway. J Neurosci 2015; 35:3190.
  71. Guha S, Rees E, Darvasi A, et al. Implication of a rare deletion at distal 16p11.2 in schizophrenia. JAMA Psychiatry 2013; 70:253.
  72. Schaaf CP, Goin-Kochel RP, Nowell KP, et al. Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: three patients with syringomyelia. Eur J Hum Genet 2011; 19:152.
  73. Bochukova EG, Huang N, Keogh J, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 2010; 463:666.
  74. Walters RG, Jacquemont S, Valsesia A, et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 2010; 463:671.
  75. Bruno DL, Anderlid BM, Lindstrand A, et al. Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes. J Med Genet 2010; 47:299.
  76. Jones KL, Gilbert EF, Kaveggia EG, Opitz JM. The MIller-Dieker syndrome. Pediatrics 1980; 66:277.
  77. Stratton RF, Dobyns WB, Airhart SD, Ledbetter DH. New chromosomal syndrome: Miller-Dieker syndrome and monosomy 17p13. Hum Genet 1984; 67:193.
  78. Dobyns WB, Stratton RF, Parke JT, et al. Miller-Dieker syndrome: lissencephaly and monosomy 17p. J Pediatr 1983; 102:552.
  79. Greenberg F, Stratton RF, Lockhart LH, et al. Familial Miller-Dieker syndrome associated with pericentric inversion of chromosome 17. Am J Med Genet 1986; 23:853.
  80. vanTuinen P, Dobyns WB, Rich DC, et al. Molecular detection of microscopic and submicroscopic deletions associated with Miller-Dieker syndrome. Am J Hum Genet 1988; 43:587.
  81. Dhellemmes C, Girard S, Dulac O, et al. Agyria--pachygyria and Miller-Dieker syndrome: clinical, genetic and chromosome studies. Hum Genet 1988; 79:163.
  82. Oostra BA, de Rijk-van Andel JF, Eussen HJ, et al. DNA analysis in patients with lissencephaly type I and other cortical dysplasias. Am J Med Genet 1991; 40:383.
  83. Nagamani SC, Zhang F, Shchelochkov OA, et al. Microdeletions including YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment. J Med Genet 2009; 46:825.
  84. Pilz DT, Macha ME, Precht KS, et al. Fluorescence in situ hybridization analysis with LIS1 specific probes reveals a high deletion mutation rate in isolated lissencephaly sequence. Genet Med 1998; 1:29.
  85. De Rijk-van Andel JF, Catsman-Berrevoets CE, Halley DJ, et al. Isolated lissencephaly sequence associated with a microdeletion at chromosome 17p13. Hum Genet 1991; 87:509.
  86. Schiff M, Delahaye A, Andrieux J, et al. Further delineation of the 17p13.3 microdeletion involving YWHAE but distal to PAFAH1B1: four additional patients. Eur J Med Genet 2010; 53:303.
  87. Tenney JR, Hopkin RJ, Schapiro MB. Deletion of 14-3-3{varepsilon} and CRK: a clinical syndrome with macrocephaly, developmental delay, and generalized epilepsy. J Child Neurol 2011; 26:223.
  88. GeneReviews: Hereditary Neuropathy with Liability to Pressure Palsies. http://www.ncbi.nlm.nih.gov/books/NBK1392/ (Accessed on January 25, 2012).
  89. Carmona-Mora P, Walz K. Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior. Curr Genomics 2010; 11:607.
  90. Greenberg F, Guzzetta V, Montes de Oca-Luna R, et al. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am J Hum Genet 1991; 49:1207.
  91. Seranski P, Hoff C, Radelof U, et al. RAI1 is a novel polyglutamine encoding gene that is deleted in Smith-Magenis syndrome patients. Gene 2001; 270:69.
  92. Slager RE, Newton TL, Vlangos CN, et al. Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet 2003; 33:466.
  93. Williams SR, Girirajan S, Tegay D, et al. Array comparative genomic hybridisation of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage sensitive loci also associated with schizophrenia, autism, and developmental delay. J Med Genet 2010; 47:223.
  94. Girirajan S, Elsas LJ 2nd, Devriendt K, Elsea SH. RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. J Med Genet 2005; 42:820.
  95. Williams SR, Zies D, Mullegama SV, et al. Smith-Magenis syndrome results in disruption of CLOCK gene transcription and reveals an integral role for RAI1 in the maintenance of circadian rhythmicity. Am J Hum Genet 2012; 90:941.
  96. Colley AF, Leversha MA, Voullaire LE, Rogers JG. Five cases demonstrating the distinctive behavioural features of chromosome deletion 17(p11.2 p11.2) (Smith-Magenis syndrome). J Paediatr Child Health 1990; 26:17.
  97. Smith AC, Dykens E, Greenberg F. Behavioral phenotype of Smith-Magenis syndrome (del 17p11.2). Am J Med Genet 1998; 81:179.
  98. GeneReviews: Smith-Magenis Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK1310/ (Accessed on January 25, 2012).
  99. Guérin-Moreau M, Colin E, Nguyen S, et al. Dermatologic features of Smith-Magenis syndrome. Pediatr Dermatol 2015; 32:337.
  100. Smith AC, Dykens E, Greenberg F. Sleep disturbance in Smith-Magenis syndrome (del 17 p11.2). Am J Med Genet 1998; 81:186.
  101. Gropman AL, Duncan WC, Smith AC. Neurologic and developmental features of the Smith-Magenis syndrome (del 17p11.2). Pediatr Neurol 2006; 34:337.
  102. Potocki L, Shaw CJ, Stankiewicz P, Lupski JR. Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]. Genet Med 2003; 5:430.
  103. Mefford HC, Clauin S, Sharp AJ, et al. Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy. Am J Hum Genet 2007; 81:1057.
  104. Nagamani SC, Erez A, Shen J, et al. Clinical spectrum associated with recurrent genomic rearrangements in chromosome 17q12. Eur J Hum Genet 2010; 18:278.
  105. Laffargue F, Bourthoumieu S, Llanas B, et al. Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome. Arch Dis Child 2015; 100:259.
  106. Moreno-De-Luca D, SGENE Consortium, Mulle JG, et al. Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am J Hum Genet 2010; 87:618.
  107. Koolen DA, Vissers LE, Pfundt R, et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 2006; 38:999.
  108. Sharp AJ, Hansen S, Selzer RR, et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 2006; 38:1038.
  109. Koolen DA, Kramer JM, Neveling K, et al. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet 2012; 44:639.
  110. Zollino M, Orteschi D, Murdolo M, et al. Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype. Nat Genet 2012; 44:636.
  111. GeneReviews: KANSL1-Related Intellectual Disability Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK24676/ (Accessed on April 09, 2014).
  112. Koolen DA, Sharp AJ, Hurst JA, et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet 2008; 45:710.
  113. Sharkey FH, Morrison N, Murray R, et al. 17q21.31 microdeletion syndrome: further expanding the clinical phenotype. Cytogenet Genome Res 2009; 127:61.
  114. Shaw-Smith C, Pittman AM, Willatt L, et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet 2006; 38:1032.
  115. GeneReviews: 17q21.31 Microdeletion Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK24676/ (Accessed on January 25, 2012).
  116. Turleau C. Monosomy 18p. Orphanet J Rare Dis 2008; 3:4.
  117. Koshy B, Mandal K, Srivastava VM, et al. Familial 18p deletion syndrome and 18p partial trisomy inherited from a mother with balanced translocation. Clin Dysmorphol 2011; 20:148.
  118. Margarit E, Morales C, Rodríguez-Revenga L, et al. Familial 4.8 MB deletion on 18q23 associated with growth hormone insufficiency and phenotypic variability. Am J Med Genet A 2012; 158A:611.
  119. McGoey RR, Gedalia A, Marble M. Monosomy 18p and immunologic dysfunction: review of the literature and a new case report with thyroiditis, IgA deficiency, and systemic lupus erythematosus. Clin Dysmorphol 2011; 20:127.
  120. Portnoï MF, Gruchy N, Marlin S, et al. Midline defects in deletion 18p syndrome: clinical and molecular characterization of three patients. Clin Dysmorphol 2007; 16:247.
  121. Xie CH, Yang JB, Gong FQ, Zhao ZY. Patent ductus arteriosus and pulmonary valve stenosis in a patient with 18p deletion syndrome. Yonsei Med J 2008; 49:500.
  122. Carvalho CA, Carvalho AV, Kiss A, et al. Keratosis pilaris and ulerythema ophryogenes in a woman with monosomy of the short arm of chromosome 18. An Bras Dermatol 2011; 86:S42.
  123. Jain N, Reitnauer PJ, Rao KW, et al. Autoimmune polyendocrinopathy associated with ring chromosome 18. J Pediatr Endocrinol Metab 2011; 24:847.
  124. Browning MJ. Specific polysaccharide antibody deficiency in chromosome 18p deletion syndrome and immunoglobulin A deficiency. J Investig Allergol Clin Immunol 2010; 20:263.
  125. GeneReviews: Alagille Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK1273/ (Accessed on January 25, 2012).
  126. GeneReviews: 22q11.2 Deletion Syndrome. http://www.ncbi.nlm.nih.gov/books/NBK1523/ (Accessed on January 25, 2012).
  127. Ben-Shachar S, Ou Z, Shaw CA, et al. 22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome. Am J Hum Genet 2008; 82:214.
  128. Nogueira SI, Hacker AM, Bellucco FT, et al. Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum. Eur J Med Genet 2008; 51:226.
  129. Rødningen OK, Prescott T, Eriksson AS, Røsby O. 1.4Mb recurrent 22q11.2 distal deletion syndrome, two new cases expand the phenotype. Eur J Med Genet 2008; 51:646.
  130. Phelan MC, Rogers RC, Saul RA, et al. 22q13 deletion syndrome. Am J Med Genet 2001; 101:91.
  131. Manning MA, Cassidy SB, Clericuzio C, et al. Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum. Pediatrics 2004; 114:451.
  132. Okamoto N, Kubota T, Nakamura Y, et al. 22q13 Microduplication in two patients with common clinical manifestations: a recognizable syndrome? Am J Med Genet A 2007; 143A:2804.
  133. Peeters H, Vermeesch J, Fryns JP. A cryptic duplication 22q13.31 to qter leads to a distinct phenotype with mental retardation, microcephaly and mild facial dysmorphism. Genet Couns 2008; 19:365.
  134. Prasad C, Prasad AN, Chodirker BN, et al. Genetic evaluation of pervasive developmental disorders: the terminal 22q13 deletion syndrome may represent a recognizable phenotype. Clin Genet 2000; 57:103.
  135. Bonaglia MC, Giorda R, Mani E, et al. Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. J Med Genet 2006; 43:822.
  136. Dhar SU, del Gaudio D, German JR, et al. 22q13.3 deletion syndrome: clinical and molecular analysis using array CGH. Am J Med Genet A 2010; 152A:573.
  137. Wilson HL, Wong AC, Shaw SR, et al. Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J Med Genet 2003; 40:575.
Topic 16648 Version 19.0

References

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