Version May 2024
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 1 through 11. Microdeletion syndromes involving chromosomes 12 through 22 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 12 to 22)" 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 CNVs 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 leading to disease in genomic disorders is a change in the copy number of a dose-sensitive gene or genes due to a deletion or duplication. This disrupts the gene(s) and alters the amount of protein produced. Other disease mechanisms include uncovering of recessive disorders, disruption of imprinted genes, and/or disruption of regulatory elements outside genes. (See "Genomic disorders: An overview", section on 'Disease mechanisms'.)
Genomic disorders are typically detected by array comparative genomic hybridization (CGH) studies (figure 2). Whole exome sequencing can identify single gene variants. Whole genome sequencing is a powerful molecular tool that can detect both CNVs and gene variants at once [1]. However, array CGH is still the preferred assay given the high cost of whole genome sequencing.
Gains or losses detected on an array can be confirmed with an independent method, such as fluorescent in situ hybridization (FISH), multiple ligation-dependent probe amplification (MLPA), or quantitative polymerase chain reaction (Q-PCR). MLPA kits are also used for the detection of CNVs. (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'.)
1p36 DELETION SYNDROME — This syndrome (MIM #607872), caused by a deletion with variable breakpoints at the distal tip of the short arm of chromosome 1, is one of the most common deletion syndromes, with a prevalence of 1:5000. It is characterized by moderate-to-severe intellectual disabilities and craniofacial dysmorphisms, including microcephaly, brachycephaly, large and persistently open anterior fontanelle, deep-set eyes, straight and thin eyebrows, posteriorly rotated and low-set ears, midface hypoplasia, flat nasal bridge, and pointy chin [2-8]. Orofacial clefting can be seen in this deletion. In addition, these patients have hypotonia, congenital heart disease (reported in 43 to 71 percent of individuals [2,4]; some may develop noncompaction cardiomyopathy), kidney anomalies, ophthalmologic abnormalities, skeletal anomalies, hearing loss, feeding difficulties (oropharyngeal dysphagia has been reported in up to 72 percent of affected individuals [4]), and hypothyroidism. Fifty percent develop seizures, and brain abnormalities are prevalent.
Several genes in the deleted region appear to have a role in multiple medical problems: matrix metallopeptidase 23B (MMP23B), gamma-aminobutyric acid type A receptor subunit delta (GABRD), SKI proto-oncogene (SKI), PR/SET domain 16 (PRDM16), potassium voltage-gated channel subfamily A regulatory beta subunit 2 (KCNAB2), arginine-glutamic acid dipeptide repeats (RERE), ubiquitination factor E4B (UBE4B), castor zinc finger 1 (CASZ1), podoplanin (PDPN), spen family transcriptional repressor (SPEN), endothelin-converting enzyme 1 (ECE1), heparan sulfate proteoglycan 2 (HSPG2), and leucine zipper protein 1 (LUZP1) [9]. Clinical features attributable to specific genes include MMP23B for large/late anterior closing fontanel; GABRD for neurodevelopmental abnormalities and seizures; SKI for intellectual disability, congenital heart defects, and orofacial clefting; PRDM16 for noncompaction dilated cardiomyopathy; RERE for intellectual disability, short stature, brain anomalies, ophthalmologic abnormalities, hearing loss, and kidney anomalies; and KCNAB2 for intellectual disability and seizures. Multiple genes appear to have some involvement in the development of cardiac anomalies and noncompaction cardiomyopathy including UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1.
Screening and monitoring studies include electroencephalogram (EEG) to check for seizures if suspected or as a baseline around one year of age, kidney ultrasound upon diagnosis to evaluate for structural anomalies, annual thyroid function tests, echocardiogram upon diagnosis and subsequently every two to three years, swallowing evaluations, and auditory brainstem response (ABR) hearing screening. Therapies essential to help with muscle tone and delays include physical, occupational, and speech therapies. Noncompaction cardiomyopathies respond well to conservative treatment [2].
DISTAL 1q21.1 DELETION SYNDROME — This 1.35 megabases (Mb) deletion is recurrent in size due to flanking segments that mediate these rearrangements. It is associated with microcephaly, intellectual disabilities (speech delay, learning disabilities), and mild dysmorphic facial features (MIM #612474) [10-12]. It is known as Class I 1q21.1 deletion due to its location in the distal area of this region (Class II deletions involve both the distal and proximal areas of the copy number region). However, the presentation is variable given incomplete penetrance and variable expressivity, and the microdeletion is seen in unaffected carriers. Other findings can include severe intellectual disabilities, seizures, cardiac abnormalities, cataracts, and genitourinary anomalies. Autism, attention deficit hyperactivity disorder (ADHD), schizophrenia, and other psychiatric abnormalities have been reported. There is no one single gene within this region whose variant(s) mimics the overall clinical phenotype.
HYDIN axonemal central pair apparatus protein 2 (HYDIN2) is the putative gene implicated in brain anomalies seen in this disorder since homozygous pathogenic variants in the paralog mouse gene cause hydrocephalus. Gap junction protein alpha 5 (GJA5) and gap junction protein alpha 8 (GJA8) are the hypothesized genes responsible for the heart phenotype (structural heart defects, atrial fibrillation) and eye abnormalities (microphthalmia, glaucoma, cataracts), respectively. Another gene deleted in the region includes chromodomain helicase DNA-binding protein 1 like (CHD1L), identified as responsible for kidney and genitourinary anomalies [13].
Screening studies include neurodevelopmental evaluations; physical, occupational, and speech therapy assessments; ophthalmology evaluation; and kidney ultrasound.
PROXIMAL 1q21.1 DELETION SYNDROME (THROMBOCYTOPENIA ABSENT RADIUS SYNDROME) — Thrombocytopenia absent radius (TAR) syndrome (MIM #274000) is characterized by hypomegakaryocytic thrombocytopenia and bilateral absent radii in the presence of thumbs [14]. The thrombocytopenia improves with age and normally disappears by school age. Other skeletal abnormalities, as well as heart and genitourinary anomalies, may occur. Non-immunoglobulin E (IgE) mediated cow's milk allergy with gastrointestinal symptoms is observed in some of these children and may exacerbate thrombocytopenia [15].
The etiology and inheritance are complex, although the syndrome is associated with a 1q21.1 deletion in the proximal area of the gene region [16,17]. This deletion extends approximately 200 kilobases (kb), contains 11 genes, and is adjacent but distal (telomeric) to the deletion previously described on 1q21.1. The deleted region contains the gene for ribonucleic acid (RNA) binding motif protein 8A (RBM8A) that encodes the Y14 subunit of exon-junction complex that carries out crucial RNA processing tasks. RBM8A is located on 1q21.1 within the minimal deleted region in 1q21.1. Patients with TAR syndrome have variants in this gene in addition to the 1q21.1 deletion; therefore, it requires two genetic changes, one each in the chromosome number 1 pair [18]. This second change consists of a low-frequency single nucleotide polymorphism (SNP) in the 5' untranslated region (5'UTR) of RBM8A or a novel SNP in the first intron of the same gene. These changes were found in 53 of 55 cases of patients with TAR syndrome in one series, with 51 also having the 1q21.1 deletion. This SNP appears to have regulatory properties and ultimately leads to a hypomorphic allele.
Screening and monitoring studies include an echocardiogram to evaluate for congenital heart disease and close monitoring of platelet counts, particularly in the first weeks to months of life.
1q43-44 MICRODELETION SYNDROME — Deletions in this region are seen in association with moderate-to-severe intellectual disability, microcephaly, dysmorphic features, and agenesis of the corpus callosum [19]. Craniofacial features described include a round face, prominent forehead, hypertelorism, flat nasal bridge, and low-set ears. Other clinical features include low birth weight, seizures, short stature, and feeding difficulties. The genes involved in the region include zinc finger and BTB domain-containing 18 (ZBTB18), which is mutated in autosomal dominant intellectual disability 22 (MIM #612337), and heterogenous nuclear ribonucleoprotein U (HNRNPU). Another gene in the region, AKT serine/threonine kinase 3 (AKT3), initially thought to cause the agenesis of the corpus callosum, has been ruled out. Gain-of-function variants in this gene cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome [20]. It is believed that the corpus callosum anomalies are the result of deletions in centrosomal protein 170 (CEP170) and/or ZBTB18 [21,22].
Screening studies include neurodevelopmental evaluations; physical, occupational, and speech therapies; brain magnetic resonance imaging (MRI) studies; electroencephalograms (EEGs); and seizures management.
2p15-16.1 DELETION SYNDROME — Deletions of this region extend between 4 and 6 megabases (Mb). Clinical features include severe intellectual disability, autism/autistic features, microcephaly, cortical dysplasia/pachygyria on brain magnetic resonance imaging (MRI), kidney abnormalities (multicystic kidneys, hydronephrosis), and camptodactyly [23,24]. Craniofacial features are characteristic and include progressive microcephaly, flat occiput, small palpebral fissures, telecanthus, broad and high nasal root, long philtrum, rounded upper vermillion border, and everted lower lips. Two genes have been identified in the area as candidates for the autism component: exportin 1 (XPO1) and orthodenticle homolog 1 (OTX1). However, subsequent studies have suggested that OTX1 deletions are associated with genitourinary abnormalities [25]. Brain malformations are associated with haploinsufficiency of BAF chromatin remodeling complex subunit BLC11A (BCL11A) [26,27].
Screening for these patients includes a neurodevelopmental and autism evaluation, brain imaging studies, a kidney ultrasound, and other evaluations for genitourinary malformations including vesicoureteral reflux (VUR).
2q23.1 DELETION SYNDROME — Deletions of 2q23.1 have been seen in association with severe intellectual disability, seizures, autism spectrum disorder, short stature, and microcephaly [28,29]. The severity of the seizures and the phenotype may suggest diagnoses such as Rett, Angelman, or Smith-Magenis syndrome. Methyl-CpG-binding domain protein 5 (MBD5), a gene involved in the deleted region, belongs to the methyl CpG-binding protein domain family that also includes the methyl-CpG-binding protein 2 (MECP2) gene mutated in Rett syndrome. MBD5 has also been implicated in autism and neurodevelopmental disorders [30,31]. Other clinical findings include coarse facial features, abnormal sleep patterns, and behavioral problems.
Screening for these patients include neurodevelopmental and autism evaluations, neurology evaluations with brain imaging studies, and electroencephalograms (EEGs). Treatment includes management of seizures and specific therapies for autism. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Autism spectrum disorder in children and adolescents: Overview of management".)
2q33.1 DELETION SYNDROME (GLASS SYNDROME) — Deletions of 2q33.1 are associated with a neurodevelopmental disorder with moderate-to-severe developmental delays, behavioral abnormalities, severe speech delay with limited or absent speech, and craniofacial dysmorphisms [32,33]. The majority of the clinical features seen in these patients are attributed to the deletion of the SATB homeobox 2 (SATB2) gene. Craniofacial anomalies include palate anomalies (clefting of the palate, high arched palate, bifid uvula) and dental anomalies (crowded dentition, macrodontia, hypodontia). The abnormal behaviors include autistic behaviors, hyperactivity, and aggressive behaviors. Feeding difficulties often occur due to palatal anomalies and hypotonia. Less frequent anomalies reported include skeletal abnormalities (osteopenia, scoliosis, pectus anomalies, kyphosis/lordosis), brain abnormalities (corpus callosum anomalies and enlarged ventricles), and seizures. Cardiovascular abnormalities were seen in 26 percent of patients in a cohort [34]. Some patients had deletions that extended to collagen type V alpha 1 chain (COL5A1), collagen type V alpha 2 chain (COL5A2), and bone morphogenetic protein receptor type 2 (BMPR2).
Screening studies include neurodevelopmental evaluations and physical, occupational, and speech therapies. Dental evaluations are recommended. Brain imaging is usually performed if seizures are present. Patients should also be assessed for skeletal anomalies. Cardiac echocardiography and electrocardiogram (ECG) are performed in patients with deletions involving COL5A1, COL5A2, and BMPR2 or those with a murmur.
2q37 DELETION SYNDROME — This deletion (MIM #600430) is often referred to as Albright hereditary osteodystrophy-like syndrome because patients with distal deletions present with mild-to-moderate intellectual disability, hypotonia, obesity, short stature, and brachydactyly with short phalanges (especially the third to fifth phalanges [brachydactyly type E]), as seen in patients with Albright syndrome [35]. Dysmorphic features include thin, highly arched eyebrows; prominent forehead; depressed nasal bridge; full cheeks; hypoplastic alae nasi; prominent nasal septum; thin upper lip; and ear anomalies [36,37].
Autism is commonly reported in this deletion [38]. Less common features include congenital heart disease (septal defects, aortic coarctation), gastrointestinal anomalies (pyloric stenosis, duodenal atresia), and central nervous system (CNS) anomalies.
The main candidate gene for the brachymetaphalangism seen in this deletion syndrome is histone deacetylase 4 (HDAC4). Mice with deletions of the homologous gene Hdac4(-/-) have severe bone malformations resulting from premature ossification of developing bones [39,40]. The obesity and intellectual disabilities may involve glypican 1 (GPC1), G protein-coupled receptor 35 (GPR35), and serine/threonine protein kinase 25 (STK25). The proposed genes for autism are gamma-2 centaurin (CENTG2) and serotonin receptor 2B (HTR2B). Pathogenic variants in the C-natriuretic peptide gene (NPPC) are known to cause short stature. This gene maps to the region and is a possible cause of the skeletal features (short stature and brachydactyly) seen in these patients [41].
Screening studies include neurodevelopmental and autism evaluations, skeletal survey including hand radiographs, endocrine evaluation, and an echocardiogram. Patients usually require physical, occupational, and speech therapy.
3pter-p25 DELETION SYNDROME — Deletion of the distal short arm of chromosome 3 (MIM #613792) is characterized by low birth weight, growth deficiency, intellectual disability, microcephaly, ptosis, telecanthus, downslanting palpebral fissures, micrognathia, postaxial polydactyly, and kidney anomalies [42-44]. Congenital heart defects (typically atrioventricular [AV] canal) occur in one-third of patients. Sensorineural hearing loss is frequently reported. The critical region for the deletion is located at 3p25 to 3p26. The deletion develops de novo in almost all cases. Haploinsufficiency of contactin 4 (CNTN4), a brain expressed gene, may play a key role in these patients' intellectual disability and autistic characteristics [45,46], although other data suggest that SET domain containing 5 (SETD5), a methyltransferase encoding gene located in 3p25, is the critical gene for intellectual disability [47,48]. Another gene in the region, bromodomain and PHD finger containing 1 (BRPF1), appears to be responsible for ptosis and blepharophimosis often seen in these patients [49].
Screening of these patients includes echocardiogram at the time of diagnosis, kidney ultrasound, ophthalmologic exams, and hearing, neurodevelopmental, and autism evaluations.
3q29 DELETION SYNDROME — Patients with this recurrent deletion (MIM #609425) have variable clinical findings despite the fact that the size of the deletion is almost identical (approximately 1.5 to 1.6 megabases [Mb]) [50,51]. The deletion encompasses 22 genes, although p21 protein-activated kinase 2 (PAK2) and discs large MAGUK scaffold protein 1 (DLG1) are candidates for the critical genes responsible for the phenotype. These genes are homologs of known X-linked genes associated with intellectual disabilities. The clinical features include mild-to-moderate intellectual disability, microcephaly (50 percent of cases), and mild dysmorphisms including a narrow face, large ears, short philtrum, and a high nasal bridge. Patients with this deletion may have autism and ataxia. A higher prevalence of psychiatric disorders, such as bipolar disorder, depression, and schizophrenia, are seen in these patients [52-57], with a reported prevalence of 28 percent [58,59]. Less frequent features include chest wall deformities, cleft lip/palate, long tapered fingers, ligamentous joint laity, horseshoe kidneys, and hypospadias.
Screening studies include brain imaging studies, kidney ultrasound, and neurodevelopmental and autism evaluations. Patients may require physical, occupational, and/or speech therapy.
4p DELETION SYNDROME (WOLF-HIRSCHHORN SYNDROME) — This syndrome (MIM #194190) is due to partial deletion of the short arm of chromosome 4 at 4p16.3. The deletion occurs de novo in approximately 87 percent of cases (approximately 80 percent involve the paternal chromosome) and in the remainder of the cases is due to a balanced translocation in one of the parents (most involve the maternal chromosome) [60-62]. The critical region for this syndrome has been narrowed to an approximately 200 kilobase (kb) region that includes the Wolf-Hirschhorn syndrome (WHS) critical region 1 (WHSCR1) and WHS critical region 2 (WHSCR2) genes [63]. WHS candidate 1 (WHSC1) gene is deleted in all known cases of WHS. This gene encodes an H3K36me3-specific histone methyltransferase (HMTase) that plays a role in transcriptional regulation. One of the factors that WHSC1 modulates is Nkx2-5, a central transcriptional regulator of cardiac development. The interaction of WHSC1 with multiple different transcription factors may account for the variability in clinical phenotype [64]. In addition, haploinsufficiency of the leucine zipper/EF hand-containing transmembrane protein gene (LETM1), which is also located in the critical region, is implicated in the seizures, motor delay, and growth restriction seen in patients with WHS [65,66]. This gene encodes a mitochondrial inner membrane protein involved in ion transport. Some patients have larger deletions that can be visually identified in karyotypes, while others have microdeletions. There is some correlation between deletion size and clinical severity [67].
The common clinical manifestations include pre- and postnatal growth restriction, microcephaly, congenital heart disease (atrial septal defect [ASD], ventricular septal defect [VSD], pulmonic stenosis [PS]), distinctive facial features with a "Greek warrior helmet" appearance of the nose due to high forehead, prominence of the glabella, hypertelorism, high and arched eyebrows, epicanthal folds, and downturned corners of the mouth. All of these patients have significant intellectual disabilities.
Patients have frequent episodes of respiratory infections due in part to recurrent aspiration. Antibody deficiencies are also common. In one series of 190 patients with WHS, immune defects occurred in approximately 4 percent of patients and included common variable immunodeficiency, immunoglobulin A (IgA) and immunoglobulin G2 (IgG2) subclass deficiency, and impaired polysaccharide responsiveness [68]. T cell immunity is normal. Immunodeficiency does not appear to correlate with deletion size. (See "Syndromic immunodeficiencies", section on 'Partial deletions of chromosome 4p (Wolf-Hirschhorn syndrome)'.)
Screening studies include neurodevelopmental evaluation and appropriate interventions. Feeding difficulties are common; therefore, swallow studies are warranted. In some instances, the placement of a gastrostomy tube may be required [69]. Cardiac evaluations should be done by echocardiography. Screening of immunoglobulin subclasses in serum is recommended to assess for humoral deficiency.
5q35 DELETION SYNDROME (SOTOS SYNDROME) — Sotos syndrome (MIM #117550), also known as cerebral gigantism, is caused by haploinsufficiency of the nuclear receptor-binding SET domain protein 1 (NSD1) gene located at 5q35 [70]. NSD1 is a histone methyltransferase that is involved in histone modification and chromatin remodeling. Deletions in the chromosomal region containing NSD1 are the most common cause of Sotos syndrome in the Japanese population [71], whereas point mutations of the NSD1 gene are the most common cause in White populations [72]. There is some overlap between this condition and Weaver syndrome that is associated with variants in enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), a gene that plays a role in methylation of H3 histones [73]. Patients with Weaver syndrome have overgrowth and camptodactyly.
Clinically, Sotos syndrome is characterized by overgrowth that is evident at birth with an increase in head circumference [74-76]. Hypotonia and delayed gross and fine motor milestones are typical. Oftentimes, these children are considered "clumsy." They have mild intellectual disabilities. Patients with Sotos syndrome have characteristic facial features, with a bossed forehead, receding hairline, hypertelorism, downslanting palpebral fissures, large ears, high-arched palate, and pointy chin. Premature teeth eruption is commonly seen. Skeletal features include scoliosis and large hands and feet. Advanced bone age is commonly seen. Brain imaging may show dilated ventricles, increased extra-axial cerebrospinal fluid (CSF), cortical atrophy spaces, and abnormalities of the corpus callosum. Cardiac anomalies, including patent ductus arteriosus (PDA) and atrial septal defect (ASD), are frequent in patients with 5q35 deletion. Kidney anomalies may include hypoplastic kidneys and hydronephrosis. (See "The child with tall stature and/or abnormally rapid growth", section on 'Cerebral gigantism'.)
The NK2 homeobox 5 (NKX2.5) gene is also located in this deletion region. This gene is associated with congenital heart disease and atrioventricular (AV) conduction defects.
Array comparative genomic hybridization (CGH) is the first line of testing if the diagnosis is suspected, followed by mutation studies if negative. Screening and monitoring studies include brain imaging, renal ultrasound, echocardiogram, and bone age. Therapy is supportive and includes referral to physical and occupational therapy.
6p25 DELETION SYNDROME — Microdeletion of distal 6p (MIM #612582) is associated with a distinctive clinical phenotype including eye abnormalities (anterior chamber dysgenesis), hearing loss, congenital heart disease, dental anomalies, developmental delay, and a characteristic facial appearance [77-79].
The facial features include a prominent forehead with turricephalic appearance (tower skull), midface hypoplasia, downslanting palpebral fissures, hypertelorism, epicanthal folds, ptosis, proptosis, ear anomalies, flat nasal bridge, short and/or smooth philtrum, and high palate [80]. Central nervous system (CNS) malformations are common, including hydrocephalus (ventriculomegaly), hypoplasia of the cerebellum (Dandy-Walker malformation), and brainstem and corpus callosum anomalies. Mild-to-moderate developmental delay is part of the syndrome. Other white matter abnormalities have been seen as part of this deletion [81]. Lastly, heart defects (ventricular septal defect [VSD]/atrial septal defect [ASD], patent foramen ovale [PFO], and patent ductus arteriosus [PDA]) have been reported.
The eye malformations seen are known as the Axenfeld–Rieger malformation and include corneal opacities, iris coloboma, and hypoplasia of the iris with adherent iris strands to the peripheral cornea. The patient is considered to have Rieger anomaly if the iris demonstrates stromal hypoplasia, the pupils are distorted, or there are extra holes in the iris [82]. The iris is normal in patients who only have the Axenfeld anomaly.
Posterior embryotoxon is a term used to describe a prominent and anteriorly displaced Schwalbe line (the anatomic line demarcating the outer limit of the corneal endothelium layer) that is seen in patients with the Axenfeld-Rieger malformation. Half of the patients with posterior embryotoxon will go on to develop glaucoma. Pathogenic variants in the human homolog of FoxC1 (mice), known as the forkhead transcription factor gene (FKHL7), cause an autosomal-dominant form of glaucoma and are probably responsible for the glaucoma phenotype seen in this deletion syndrome [83,84]. Forkhead box C1 (FOXC1), forkhead box F2 (FOXF2), and forkhead box Q1 (FOXQ1), which are part of the forkhead family of genes, are involved in the deletion and also appear to play a significant role in this disorder [85].
Careful ophthalmologic evaluations are needed, especially for patients with posterior embryotoxon, given their increased risk for glaucoma. Other screening and monitoring studies include an echocardiogram, brain imaging studies, audiology evaluations including auditory brainstem response (ABR) testing, and neurodevelopmental evaluation. Patients typically benefit from physical, occupational, and speech therapy.
7q11.23 DELETION SYNDROME (WILLIAMS SYNDROME) — This syndrome, also known as Williams-Beuren syndrome (WBS; MIM #194050), results from a heterozygous deletion of approximately 1.6 megabases (Mb) at 7q11.23 [86,87]. The deletion includes the elastin (ELN) gene [88]. Cardiovascular abnormalities are frequent and are related to elastin haploinsufficiency. These abnormalities include supravalvular aortic stenosis (in 70 percent of cases), pulmonic valve stenosis, and renal artery stenosis. Kidney abnormalities are also seen. (See "Williams syndrome".)
Other clinical features include constipation, which is often significant and is associated with an increased risk for diverticulosis and diverticulitis; failure to thrive; and sensorineural or conductive hearing loss [86,87,89,90]. Classical facial features include periorbital fullness of subcutaneous tissues, hypertelorism, stellate pattern of the iris, long philtrum, thick vermillion border of the lips, wide mouth, and small jaw (often referred to as elfin facies) [86,87]. Idiopathic hypercalcemia is observed and is frequently transient.
Mild-to-moderate intellectual disability is common, with uneven cognitive disabilities. Verbal and memory performance is less impaired than visual-spatial perception [91]. Young patients with WBS tend to be very social, gregarious, and often overly friendly with strangers. Haploinsufficiency of the general transcription factor IIi (GTF2I) and GTF2I repeat domain containing 1 (GTF2IRD1) genes appears to lead to the increased social interactions seen in patients with WBS [92,93]. Behavioral abnormalities include anxiety and attention deficit disorder [94].
Screening of these patients should include echocardiography, kidney ultrasound with special attention to the renal artery, serum calcium, neurodevelopmental evaluations, and audiology evaluations including auditory brainstem response (ABR) testing.
8q22.1 DELETION SYNDROME (NABLUS MASK-LIKE FACIAL SYNDROME) — Deletions in the 8q21.3-q22.1 region that include a 2.79 megabase (Mb) region at 8q22.1 are associated with the Nablus mask-like facial syndrome (MIM #608156) [95,96]. This rare condition has a striking phenotype that is characterized by severe blepharophimosis (bilateral ptosis with reduced lid size); glistening, tight-appearing facial skin; sparse and unruly hair; a flat and broad nose; and ears that are small and triangular in shape, with prominent antihelices and unfolded helices [97]. Other anomalies include acquired microcephaly and submucous cleft palate. Hand anomalies include contractures and interdigital webbing. Developmental delay is also reported.
A smaller deletion (1.6 Mb) in the 8q22.1 region was associated with speech delay and autism spectrum disorder but not the other features noted with the larger deletion [98].
Patients will need ophthalmologic and plastic surgery evaluations for the surgical correction of blepharophimosis. In addition, patients with speech and/or swallowing abnormalities should be evaluated for submucous cleft palate. Developmental evaluations and referral for physical, occupational, and/or speech therapy may also be required.
8q24.11 DELETION SYNDROME (LANGER-GIEDION SYNDROME OR TRICHORHINOPHALANGEAL SYNDROME TYPE II) — Patients with this syndrome (MIM #105230) present with multiple dysmorphic facial features including large, laterally protruding ears; a bulbous nose; and an elongated upper lip [99-102]. Additional clinical features include sparse scalp hair, winged scapulae, multiple cartilaginous exostoses, redundant skin, and intellectual disabilities. Skeletal findings also include cone epiphyses that are easily detected by hand radiographs. Tibial hemimelia has also been reported [103].
The 8q24.11 deletion involves exostosin glycosyltransferase 1 (EXT1; MIM #133700), the gene responsible for the exostoses.
Trichorhinophalangeal syndrome (TRPS) type I is an autosomal dominant disorder with similar findings to TRPS type II, including the facial and skeletal findings (cone epiphyses) [104]. However, patients with type I do not have intellectual disabilities or exostoses. TRPS type I is caused by pathogenic variants in the transcriptional repressor GATA binding 1 (TRPS1) gene, located in the 8q24.1 region. Therefore, haploinsufficiency of TRPS is directly related to most of the clinical features seen in this disorder.
Skeletal surveys are performed to assess for exostoses and bone deformities. Patients may require developmental evaluations and referral to physical, occupational, and/or speech therapy.
9p22 DELETION SYNDROME — The clinical manifestations of this syndrome consist of intellectual disability, trigonocephaly, midface hypoplasia, upward-slanting palpebral fissures, short nose with depressed nasal bridge, long philtrum, and micrognathia [105-107]. The trigonocephaly appears to be the result of deletions in the FRAS1-related extracellular matrix 1 (FREM1) gene located in the region [108].
Most of these cases are due to a de novo deletion of the distal portion of the short arm of chromosome 9 [105,107]. The deletion occurs with similar frequency among chromosomes of paternal and maternal origin. Therefore, genomic imprinting does not seem to play a role [107]. The critical region for the 9p deletion syndrome maps to a 4 to 6 megabase (Mb) region in 9p22-9p23.
Screening for these patients should include neurodevelopmental evaluations, echocardiogram to assess structural heart defects, and referral to a craniofacial surgeon to address trigonocephaly when present [109].
9q34.3 DELETION SYNDROME OR 9q SUBTELOMERE DELETION SYNDROME — This syndrome, also called Kleefstra syndrome (MIM #610253), is characterized by moderate-to-severe intellectual disability with severe speech delay, hypotonia, microcephaly and/or brachycephaly, hypertelorism, synophrys (joined eyebrows) and/or arched eyebrows, midface hypoplasia, a short nose with upturned nares, a protruding tongue with everted lower lip, and downturned corners of the mouth [110,111]. Some children may have mild intellectual disability, highlighting the wide variability in this condition. On average, there is significant discrepancy in language, with expressive communication more severely affected than receptive communication; therefore, persons with Kleefstra syndrome may be able to use sign language or Augmentative Alternative Communications (AAC) devices [112].
Patients with this deletion often have congenital heart defects (primarily atrial septal defect [ASD] or ventricular septal defect [VSD], tetralogy of Fallot, aortic coarctation, bicuspid aortic valve, and pulmonic stenosis). Approximately half of patients have seizures (tonic-clonic, absence, complex partial seizures, and generalized seizure with focal onset). Febrile seizures are common. Behavioral abnormalities include maladaptive behaviors (aggression, hyperactivity, self-mutilation) and autistic spectrum features [113]. Psychiatric disorders including mood disorders, psychosis, extreme apathy, and catatonic-like features have been reported after puberty. Sleep disturbances are reported and can be severe. Other features include eye anomalies such as severe hypermetropia; sensorineural and/or conductive hearing loss; genitalia anomalies in males such as hypospadias, cryptorchidism, and small penis; and kidney defects with vesicoureteral reflux, hydronephrosis, kidney cysts, and chronic kidney insufficiency. Growth is within normal early on, although with a tendency toward obesity after age two years [112,114].
The 9q34.3 deletion syndrome is caused by haploinsufficiency of the euchromatic histone lysine methyltransferase 1 (EHMT1) gene [115]. The product of this gene is a histone H3 Lys 9 (H3-K9) methyltransferase involved in histone methylation. Most patients with Kleefstra syndrome have this microdeletion, but some have pathogenic variants of the EHMT1 gene [116]. The loss of other genes in the same region may cause additional clinical manifestations. The deletion of the distal long arm of chromosome 9 can be detected with subtelomeric fluorescent in situ hybridization (FISH), multiple ligation-dependent probe amplification (MLPA), and/or array comparative genomic hybridization (CGH).
Screening studies include developmental/autism evaluations, ophthalmologic evaluations, echocardiogram, kidney ultrasound, and electroencephalogram (EEG). Patients require physical, occupational, and/or speech therapy.
10p14-p13 DELETION (DiGEORGE SYNDROME TYPE II) — A second locus for DiGeorge syndrome was recognized in patients with 10p deletions that presented with conotruncal heart defects, hypoparathyroidism, and T cell immunodeficiency (MIM #146255) [117-121]. These patients also have sensorineural hearing loss, which is not typically present in patients with DiGeorge syndrome type I (22q11.2 deletion). GATA-binding protein 3 (GATA3), the critical gene for this disorder, is essential for development of the parathyroid gland, auditory system, and kidneys [122]. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Defects on other chromosomes'.)
Patients with this deletion should have hearing evaluations and renal ultrasound, in addition to the usual screening studies in patients with DiGeorge syndrome. (See "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis".)
11p13 DELETION SYNDROME (WAGR SYNDROME) — WAGR is an acronym that defines a group of abnormalities that include Wilms tumor, Aniridia, Genitourinary anomalies, and Range of developmental delays (intellectual disability; MIM #194072). Ophthalmologic findings include aniridia, cataracts, glaucoma, and nystagmus. The most common abnormalities of the genitourinary tract are cryptorchidism in males and streak ovaries and bicornuate uterus in females. Ambiguous genitalia have been reported in males and females. WAGR syndrome and Wilms tumor are reviewed in greater detail separately. (See "Presentation, diagnosis, and staging of Wilms tumor", section on 'WAGR syndrome'.)
WAGR syndrome is a contiguous gene deletion syndrome. Deletions of WT1 transcription factor (WT1) are responsible for Wilms tumor, while paired box 6 (PAX6) deletions are responsible for aniridia [123]. The aniridia affects the entire ocular globe, resulting in microphthalmia, glaucoma, lens cataracts and subluxation, foveal hypoplasia, and optic nerve coloboma/hypoplasia. PAX6 and WT1 are proximally located within 11p13. There is a different entity known as Denys-Drash syndrome (kidney nephropathy, gonadal anomaly, predisposition to Wilms tumor) that is associated with WT1 pathogenic variants. In addition, there are reports of larger deletions combining WAGR and Potocki-Shaffer syndrome [124].
Patients with WAGR require aggressive kidney surveillance, with kidney ultrasounds every three months until age eight years. The risk for Wilms tumor in patients with WT1 deletions is on average 50 percent, although reported to be as high as 77 percent, and up to 40 percent of survivors with Wilms tumors will progress to end-stage kidney disease (ESKD) [125]. Of those affected with Wilms tumor, 90 percent develop tumors before age four years, and 98 percent before age seven years. Intellectual disability is variable, and 70 percent have mild-to-moderate intellectual disability. Some patients have normal intellect.
Patients with WAGR should have ophthalmologic evaluations every six months not only to assess morphologic changes but to evaluate for glaucoma, corneal changes, and refraction abnormalities. Kidney ultrasound should be performed every three months. Follow-up with a pediatric oncologist is recommended until eight years of age. Developmental evaluations should be performed as appropriate for age, and, if delays detected, therapies should be instituted as needed.
11p11.2 DELETION SYNDROME (POTOCKI-SHAFFER SYNDROME) — This is a contiguous gene deletion syndrome characterized by the presence of parietal foramina, abnormal craniofacial features, moderate-to-severe developmental delay, and exostoses (MIM #601224) [124,126,127]. The parietal foramina appear related to deletions in ALX homeobox 4 (ALX4), and the exostoses are secondary to deletions of exostosin glycosyltransferase 2 (EXT2) gene [128,129]. Studies of translocations in this region suggest that the intellectual disability and craniofacial anomalies seen in this syndrome are due to haploinsufficiency of PHD finger protein 21A (PHF21A), a protein involved in histone methylation that mediates repression of neuron-specific genes [130].
Screening studies include a skeletal survey, magnetic resonance imaging (MRI) of the brain, kidney ultrasound, and laboratory studies including a complete blood count, comprehensive metabolic panel, thyroid studies, and urinalysis [131].
11q24.1 DELETION SYNDROME (JACOBSEN SYNDROME) — Distal deletions of the long arm of chromosome 11 are associated with a condition known as Jacobsen syndrome (MIM #147791). More than 90 percent of these patients have Paris-Trousseau syndrome, characterized by thrombocytopenia and platelet dysfunction that typically normalizes over time [132-134]. More than half have serious congenital heart defects, including hypoplastic left heart syndrome, coarctation of the aorta, type B truncus arteriosus, and double outlet right ventricle. Recurrent infections of the upper respiratory system are common. Short stature and insulin-like growth factor 1 (IGF-1) deficiency are also frequently seen. (See "Hypoplastic left heart syndrome: Anatomy, clinical features, and diagnosis" and "Causes of thrombocytopenia in children", section on 'Large or giant platelets'.)
These patients have dysmorphic craniofacial features, including hypertelorism, downslanting palpebral fissures, ptosis, sparse eyebrows, broad nasal bridge with short nose and anteverted nares, thin upper lip, V-shaped mouth, and high-arched palate. Other abnormalities include structural renal defects (duplicated ureters, single kidney, and hydronephrosis), genitourinary anomalies (undescended testes, hypospadias), and gastrointestinal anomalies (pyloric stenosis, constipation). Limb anomalies include syndactyly of hands and feet, fifth digit clinodactyly, and toe anomalies.
Cognitive function ranges from normal intelligence to moderate intellectual disability. Nearly half of the patients have mild intellectual disability, with a characteristic neuropsychiatric profile demonstrating near-normal receptive language ability but mild-to-moderate impairment in expressive language. Up to 47 percent of these patients were found to have autism spectrum disorder. The critical region involved in autism includes the Rho GTPase-activating protein 32 (ARHGAP32) gene that encodes a rho guanosine triphosphate hydrolase (GTPase)-activating protein [135].
This syndrome can sometimes be diagnosed with conventional cytogenetic studies. Use of array comparative genomic hybridization (CGH) has redefined the phenotype and narrowed the critical region. Deletion of at least three out of the four platelet function critical genes that reside in the area, ETS proto-oncogene 1 transcription factor (ETS1), Fli-1 proto-oncogene ETS transcription factor (FLI1), nuclear factor related to kappa B binding protein (NFRKB), and junctional adhesion molecule 3 (JAM3), are apparently needed to develop thrombocytopenia, and deletions of potassium inwardly rectifying channel subfamily J member 1 (KCNJ1) and ADAM metallopeptidase with thrombospondin type 1 motif 15 (ADAMTS15) may contribute to the kidney anomalies [136]. Heterozygous losses involving the FL-1 gene appear to cause dysmegakaryocytopoiesis and Paris-Trousseau thrombocytopenia [137]. The heart genes are not yet identified, although ETS1 is still under consideration.
Screening studies include an echocardiogram, kidney ultrasound, neurodevelopmental evaluations, and monitoring of platelet and coagulation function.
SUMMARY
●Definition of 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.)
●Definition and types 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 'Overview of genomic disorders' above.)
●1p36 deletion syndrome – 1p36 deletion syndrome (MIM #607872) is one of the most common microdeletion syndromes. It is characterized by moderate-to-severe intellectual disabilities and craniofacial dysmorphisms. In addition, these patients have hypotonia, congenital heart disease, kidney and skeletal anomalies, ophthalmologic abnormalities, hearing loss, feeding difficulties, and hypothyroidism. Brain abnormalities and seizures may also occur. (See '1p36 deletion syndrome' above.)
●4p deletion syndrome (Wolf-Hirschhorn syndrome [WHS]) – 4p deletion syndrome (WHS; MIM #194190) is characterized by pre- and postnatal growth restriction, microcephaly, congenital heart disease, significant intellectual disabilities, and distinctive facial features with a "Greek warrior helmet" appearance. (See '4p deletion syndrome (Wolf-Hirschhorn syndrome)' above.)
●7q11.23 deletion syndrome (Williams or Williams-Beuren syndrome [WBS]) – The common clinical features of 7q11.23 deletion syndrome (Williams or Williams-Beuren syndrome [WBS], MIM #194050) include cardiovascular and kidney abnormalities, failure to thrive, sensorineural hearing loss, constipation, and classical facial features often referred to as "elfin facies." (See '7q11.23 deletion syndrome (Williams syndrome)' above.)
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