Microduplication syndromes

INTRODUCTION — Microduplications, or submicroscopic duplications, are chromosomal duplications that are too small to be detected by light microscopy using conventional cytogenetics methods. Specialized testing is needed to identify these duplications. Microduplications are typically one to three megabases (Mb) long and involve several contiguous genes. The exact size and location of a microduplication that causes a syndrome may vary, but a specific "critical region" may be consistently involved. Most of the phenotypic effects of these microduplications are due to changes in a few critical dose-sensitive genes or, in some cases, a single gene if a duplication disrupts its integrity.

The phenotype of microduplication syndromes is often less clear and less well defined than for the corresponding microdeletion syndrome. In addition, some microduplication syndromes may be inherited from apparently normal parents, raising important issues regarding incomplete penetrance and ascertainment bias in these newly described clinical entities.

This topic reviews microduplication syndromes of chromosomes 1 to 22. Microdeletion syndromes, congenital abnormalities of the sex chromosomes, and other congenital chromosomal abnormalities, such as trisomies, are reviewed in detail elsewhere. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion syndromes (chromosomes 12 to 22)" 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/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 those resulting from 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 (CGH) (figure 2). Most 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'.)

1q21.1 DUPLICATION SYNDROME — Recurrent duplications in this region encompassing approximately 1.35 megabases (Mb) are associated with macrocephaly and mild intellectual disabilities (speech delay, learning disabilities; MIM #612475) [1,2]. Psychiatric conditions, such as schizophrenia in adult patients [3], and attention deficit hyperactivity disorder (ADHD) have also been reported. Other developmental disorders, such as autism spectrum disorders, have been reported in up to 41 percent of cases [4]. Autism is most commonly observed in patients with duplications rather than deletions of this region. Abnormalities in brain imaging, including periventricular heterotopia, dilated ventricles, reduced corpus callosum, and Chiari I malformation, were observed in many cases [4]. Other studies have reported congenital heart disease, such as tetralogy of Fallot and pulmonary stenosis, among these patients [3,5]. The clinical presentation of this disorder is variable due to incomplete penetrance and variable expressivity. Thus, this microduplication is also seen in asymptomatic persons. Hydrocephalus-inducing, mouse, homolog of (HYDIN2) is the gene implicated in this disorder. Novel NOTCH-like genes like notch 2 N-terminal-like (NOTCH2NL) A, B, and C located in the 1q21.1 region play a role in the rapid evolution of human neocortex growth and cortical neuron differentiation [6]. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on 'Distal 1q21.1 deletion syndrome'.)

Neurodevelopmental evaluations and brain imaging studies are recommended. Older patients should be assessed for later-onset psychiatric conditions such as schizophrenia. Cardiac echocardiography should be performed in patients with suspected congenital heart disease. Patients may benefit from physical, occupational, and speech therapies.

2q31 DUPLICATION SYNDROME — Duplications in this region encompassing the homeobox D (HOXD) gene cluster, as well as metaxin 2 (MTX2) and even-skipped homeobox 2 (EVX2), have been reported in patients with mesomelic dysplasia with shortening of the arms and legs, also known as mesomelic dysplasia Kantaputra type [7,8].

Patients with this duplication would benefit from a skeletal survey to assess for possible skeletal abnormalities.

2q23.1 DUPLICATION SYNDROME — Duplications of this region vary in size, but the common link is the involvement of the methyl-CpG binding domain protein 5 (MBD5) gene. Duplications in this region have been linked to intellectual disability, autism spectrum disorder, language delays, infantile hypotonia with gross motor delays, and behavioral abnormalities [9-11].

Neurodevelopmental evaluation, including testing for autism spectrum disorders, is recommended.

3q29 DUPLICATION SYNDROME — This recurrent duplication has variable clinical findings and is the reciprocal rearrangement of the 3q29 microdeletion. p21 protein-activated kinase 2 (PAK2) and discs large, drosophila, homolog of, 1 (DLG1) are the critical gene candidates. Other genes contained in the region, including 3-hydroxybutyrate dehydrogenase 1 (BDH1), F-box protein 45 (FBXO45), and transferrin receptor (TFRC), are linked to neuronal development [12]. Clinical findings include microcephaly; macrocephaly; structural brain anomalies; distinctive facial features (low-set, simple ears; downturned corners of the mouth; long, bushy eyebrows; long eyelashes; high nasal bridge); eye abnormalities (microphthalmia, cataracts, irides colobomas); cleft palate; and renal and cardiac anomalies (MIM #611936) [13-16]. Mild-to-moderate intellectual disabilities are common, and patients may have speech delay. However, this duplication has been seen in apparently unaffected individuals. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on '3q29 deletion syndrome'.)

Brain imaging studies are recommended given the association with structural brain abnormalities. Other screening studies include renal ultrasound, echocardiogram, and funduscopic eye exam. Patients may benefit from physical, occupational, and speech therapies.

5q35 MICRODUPLICATION SYNDROME — 5q35 is the Sotos syndrome critical region that contains the Sotos syndrome gene, also known as nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1 (NSD1). This gene encodes the nuclear receptor-binding SET domain protein 1, which is part of histone methyltransferase complex. These proteins participate in chromatin integrity, and many other demethylases have been implicated in neurodevelopmental disorders [17]. The 5q35 microduplication syndrome is basically a reverse of the Sotos syndrome (overgrowth) phenotype [18,19]. Patients with duplications involving NSD1 present with microcephaly, global developmental delay, short stature, growth retardation, and delayed bone age. Dysmorphic features have been reported, as well as behavioral, ocular, and mild hand anomalies [20]. Seizures have been reported in some patients. Psychiatric phenotypes have been described in older affected persons [17]. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on '5q35 deletion syndrome (Sotos syndrome)'.)

Recommended screening studies include brain magnetic resonance imaging (MRI) and electroencephalogram (EEG). Growth should be monitored.

7q11.23 DUPLICATION SYNDROME (WILLIAMS-BEUREN REGION DUPLICATION SYNDROME) — Deletions in this region are associated with Williams syndrome (MIM #609757). The reciprocal recurrent 1.5 to 1.8 Mb duplication causes a different clinical phenotype characterized by hypotonia and global developmental delay, with speech delay that can range from moderate to severe. Many of these patients have been diagnosed with autism spectrum disorders [21,22]. Other behavioral abnormalities include oppositional behaviors, anxiety, attention deficit hyperactivity disorder (ADHD), and variable levels of aggression [23,24]. Dysmorphic features are mild and without a clear characteristic pattern. Brain abnormalities have been observed and seizures reported [25]. Other findings were demonstrated in one clinical series, including joint hyperextensibility and tendency to fracture with minimal trauma. In addition, this study showed some improvements of reciprocal social behaviors over time [26]. The gene(s) responsible for the phenotype are not yet known. Aortic dilatation has been reported at different ages in up to 46 percent of these patients [27,28]. Renal and genitourinary anomalies, such as renal and gonadal agenesis, are also seen in this condition [28].

Hearing evaluations are recommended to rule out other causes of speech delay. Other screening studies include speech evaluation, brain magnetic resonance imaging (MRI), and electroencephalogram (EEG). Renal ultrasound is recommended to rule out structural genitourinary anomalies. Echocardiograms are warranted at the time of diagnosis and thereafter every two to three years to rule out dilatation that could be addressed by medical or surgical treatment. Referral to speech therapy is recommended.

11p15 DUPLICATIONS IN BECKWITH-WIEDEMANN SYNDROME — Beckwith-Wiedemann syndrome (BWS; MIM #130650) can be caused by microduplication of the 11p15 region originating in the paternal chromosome. The major clinical features of this syndrome are macrosomia, macroglossia, omphalocele, prominent eyes, ear creases, large kidneys, hyperplasia of pancreas, and hemihypertrophy. BWS is discussed in greater detail separately. (See "Beckwith-Wiedemann syndrome".)

15q11-13 DUPLICATION SYNDROME — Deletion of this imprinted region causes Angelman/Prader-Willi syndromes depending on the parental origin. Gains and duplications of this region are seen in persons with intellectual disability and autism (MIM #608636) [29-31]. In most cases, the delays and autism phenotypes are associated with duplication of the maternally inherited allele [32,33]. These patients may also present with hypotonia, global developmental delay, attention deficit hyperactivity disorder (ADHD), ataxia, and seizures. The Angelman syndrome gene, ubiquitin-protein ligase E3A (UBE3A), is the gene potentially responsible for the autism. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)' and "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 paternal deletion syndrome (Prader-Willi syndrome)'.)

Formal developmental and autism evaluations are recommended. Assessment of seizures includes an electroencephalogram (EEG). (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'.)

15q13.3 DUPLICATION SYNDROME — This 1.5 megabase (Mb) microduplication is reciprocal to the 15q13.3 deletion and extends between breakpoints BP4 and BP5. One-half of persons ascertained with this duplication have a range of neuropsychiatric disorders [34]. Patients with these duplications may present with neuropsychiatric problems including attention deficit hyperactivity disorder (ADHD), speech delays, autism spectrum disorder, and schizophrenia [35-37]. Seizures have also been reported [38]. The duplication contains the alpha 7 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA7) gene, believed to be the main player in the behavioral abnormalities [39]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q13.3 deletion syndrome'.)

Formal neurodevelopmental evaluations are recommended, especially for those presenting with developmental delays and behavioral problems.

15q24 DUPLICATION SYNDROME — This is the reciprocal duplication of the 15q24 deletion (MIM #613406). The cases described share similar clinical features with the deletion syndrome, including mild intellectual disability, receding anterior hairline, broad medial eyebrows, hypertelorism, epicanthal folds, downslanting palpebral fissures, broad nasal base and high nasal bridge, full lower lip, joint laxity, and in some cases, contractures, as well as hypospadias and genital anomalies in males [40,41]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q24 deletion syndrome'.)

Formal developmental evaluations are recommended. Endocrine and urology evaluation is performed in males if needed. Patients may benefit from physical, occupational, and speech therapies.

16p13.3 DUPLICATION SYNDROME — This duplication involves the Rubinstein-Taybi critical region and includes the cyclic adenosine monophosphate [cAMP] response element-binding protein [CREB] binding protein (CREBBP) gene. Clinical features include normal growth, mild-to-moderate developmental delay, small and proximally implanted thumbs, long fingers, and mild arthrogryposis (multiple joint contractures) with camptodactyly (flexion deformities of the proximal interphalangeal joints). Dysmorphic features include deep-set eyes, narrow palpebral fissures, wide nasal bridge, long philtrum, and thin upper lip. This duplication is occasionally associated with heart defects (atrial septal defect [ASD], tetralogy of Fallot [TOF]), submucous cleft palate anomalies, and eye anomalies (strabismus, blepharophimosis, and ptosis). The penetrance of this duplication is variable since it has been found in normal transmitting parents [42,43].

Neurodevelopmental evaluations are recommended. Other screenings should include an echocardiogram and a cardiac evaluation. Patients may benefit from physical, occupational, and speech therapies.

16p13.11 DUPLICATION SYNDROME — Clinical findings for this duplication that spans approximately 1.65 megabases (Mb) include behavioral abnormalities, cognitive impairment, autism, congenital heart defects, and skeletal manifestations, such as hypermobility, craniosynostosis, and polydactyly. During the perinatal period, feeding difficulties and low muscle tone are common, while learning disabilities and speech delays are more frequently reported later in childhood (>80 percent of patients). This duplication is considered a risk factor for neuropsychiatric disorders [44-46].

Formal developmental evaluation is recommended for those with developmental delays and behavioral concerns.

16p11.2 DUPLICATION SYNDROME — This recurrent rearrangement is the reciprocal event of the deletion in 16p11.2 that spans almost 600 kb. There is significant variability in the clinical manifestations, ranging from normal in the majority of cases to developmental delay and autistic spectrum disorders [47-51]. A number of other neurodevelopmental and behavioral disorders have been observed as well [52]. This duplication is associated with an increased risk for seizure disorders such as infantile spasms [53] and Rolandic epilepsy [54]. One study describing a larger cohort of 57 patients with this duplication described neurologic findings that ranged from tremors, symmetric limb hypotonia, hyperreflexia, hyporeflexia, truncal hypotonia, and articulation disorders [55]. Other clinical findings seen in patients with this duplication include thoracolumbar syringomyelia [56]. Changes in copy number variations (CNVs) in this locus (ie, losses or gains) modulate cognition, including language, verbal memory, and inhibition [57]. Patients with this copy number gain have a smaller head circumference and lower body mass index (BMI; 0.6 points lower) than controls within the family [58]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '16p11.2 deletion syndrome'.)

Formal developmental and autism evaluations are recommended in affected patients. Electroencephalography (EEG) evaluation is indicated in patients with clinically suspected seizures. A spin magnetic resonance image (MRI) should be considered since syringomyelia may be asymptomatic. Thorough clinical neurologic evaluations or a neurology referral are recommended.

17p13.3 DUPLICATION SYNDROME — While deletions in the distal short arm of chromosome 17 cause Miller-Dieker lissencephaly syndrome, duplications in this region are associated with developmental delay, central nervous system (CNS) anomalies, and autism spectrum disorder (MIM #613215) [59]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '17p13.3 deletion syndromes'.)

There are two duplication types: class I and class II. The critical region for class I spans 258 kb and includes six genes: exons 2 to 3 of tumor suppressor candidate 5 (TUSC5), tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon isoform (YWHAE), v-crk avian sarcoma virus CT10 oncogene homolog (CRK), myosin IC (MYO1C), sphingosine kinase 1 (SPHK1) interacting protein (SKIP), and exons 1 to 4 of phosphatidylinositol transfer protein, alpha (PITPNA). It appears that YWHAE plays the main role in the CNS anomalies and autism phenotype, while CRK seems to be the gene responsible for growth restriction. However, subsequent reports have indicated that the duplications of CRK can be associated to overgrowth [60]. The class I duplication may include the basic helix-loop-helix family member a9 (BHLHA9) gene. Duplications in this gene are linked to split-hand/foot malformation with long-bone deficiency (SHFLD) [61], although it appears that duplications of this gene alone are not enough to cause SHFLD [62].

The class II duplication additionally includes platelet-activating factor acetylhydrolase, isoform 1B, alpha subunit; formerly LIS1 (PAFAH1B1/LIS1), the lissencephaly gene responsible for lissencephaly type I.

Clinical findings for class I duplications include autistic features, behavioral problems, speech and motor delays, macrosomia, mild dysmorphic features (or none), hand and feet malformations (large hands, small distal phalanges), and overgrowth (a rare feature for a chromosomal/genomic disorder). Class II duplications show a range from normal intellect to severe intellectual disability, hypotonia that can be severe, autism, attention deficit hyperactivity disorder (ADHD), microcephaly, dysmorphic features, and severe growth restriction. There are no migration abnormalities in the brain even though PAFAH1B1 is involved. A number of structural CNS abnormalities involving the corpus callosum, cerebellar vermis, and cranial base have been reported in this group [62]. PAFAH1B1 overexpression appears to lead to smaller brains based upon animal studies [63]. Other abnormalities for class II duplications include craniosynostosis, intestinal malrotation, scoliosis, cardiovascular anomalies, and other skeletal anomalies.

Formal developmental and autism evaluations are recommended. A brain magnetic resonance image (MRI) is also recommended in patients with class II duplications. Patients may benefit from physical, occupational, and speech therapies.

17p11.2 DUPLICATION SYNDROME (CHARCOT-MARIE-TOOTH TYPE 1A DISEASE) — Recurrent 1.5 megabase (Mb) duplications in 17p11.2 involving the peripheral myelin protein 22 (PMP22) gene are responsible for Charcot-Marie-Tooth type 1A (CMT1A) disease (MIM #118220). PMP22 is a dose-sensitive gene that causes CMT1A when overexpressed and hereditary neuropathy with liability to pressure palsy (HNPP) when deleted. CMT1A is a demyelinating motor-sensory neuropathy clinically characterized by progressive distal neuromuscular weakness. These patients present with foot and ankle problems including pain, weakness, deformity, and paresthesias. Foot drop and bilateral pes cavus are common. The muscles are wasted distally and conserved proximally. CMT1A is discussed in greater detail separately. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis" and "Microdeletion syndromes (chromosomes 12 to 22)", section on '17p11.2 deletion syndrome (Hereditary neuropathy with liability to pressure palsy)'.)

17p11.2 DUPLICATION SYNDROME (POTOCKI-LUPSKI SYNDROME) — This duplication, also known as Potocki-Lupski syndrome (PLS; MIM #610883), is reciprocal to the deletion on chromosome 17 that is responsible for Smith-Magenis syndrome [64-66]. The common duplication spans 3.7 megabases (Mb), but the critical region spans 1.3 Mb and includes the retinoic acid receptor 1 (RAI1) gene, a dose-sensitive gene presumably involved in the neurobehavioral and autism phenotype seen in these patients [67]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '17p11.2 deletion syndrome (Smith-Magenis syndrome)'.)

The clinical findings include infantile hypotonia, failure to thrive, intellectual disability, poor feeding, oropharyngeal dysplasia, and sleep apnea (obstructive and central sleep apnea with hypercarbia) [64,65,68]. Speech development is significantly impaired, with delays, absent speech, delayed echolalia, and verbal apraxia. Autistic spectrum disorders are seen. Structural cardiovascular abnormalities (septal defects) are part of the spectrum and can be rather severe, including hypoplastic left heart [66,69]. White matter abnormalities on brain magnetic resonance imaging (MRI) have been reported. In addition, electroencephalogram (EEG) tracings may show a common pattern with diffuse rhythmic activity during sleep [70].

Formal developmental and autism evaluations are recommended. Other screening studies include a brain MRI, echocardiogram, swallowing evaluations, and sleep studies. Referral to physical, occupational, and speech therapies is recommended.

17q12 DUPLICATION SYNDROME — This duplication is reciprocal to the deletion encompassing the hepatic nuclear factor 1 (HNF1) gene that causes cystic renal disease and maturity-onset diabetes of the young (MODY). Patients with these duplications have cognitive delays, speech delays, and behavioral problems [71]. Seizures are seen in up 70 percent of patients, and autistic behaviors and stereotypical movements are also reported [72]. Other developmental disorders in affected persons include schizophrenia and maladaptive behaviors. Additional findings include eye/vision problems in up to one-third of patients and cardiac and renal anomalies. Approximately 90 percent are inherited, while 10 percent are de novo [73]. Additional findings in these patients include excessive growth, skeletal anomalies, dysmorphic features, and other endocrine abnormalities.

Developmental evaluations are recommended, with appropriate therapies for identified problems. Endocrinology, cardiology, and neurology referrals may be indicated [74].

17q21.31 DUPLICATION SYNDROME — This duplication involves the microtubule-associated protein Tau (MAPT) and corticotropin-releasing hormone receptor 1 (CRHR1) genes (MIM #613533) and is similarly mediated by the inversion repeats flanking the MAPT gene as seen in the deletion. In the few reports of this duplication, it is associated with variable clinical features that range from normal cognition to severe intellectual disability, hypotonia, and joint laxity [75]. Poor social interactions and behavioral abnormalities have been reported in patients with this duplication [76]. A study in Alzheimer disease (AD) showed 4 patients out of 552 persons with early AD with duplications in this region [77]. In addition, brain accumulation of the Tau-associated protein can clinically mimic AD [78]. Further reports are required to determine the clinical range of this duplication. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '17q21.31 deletion syndrome'.)

Formal developmental and autism evaluations are recommended.

22q11.2 DUPLICATION SYNDROME — Duplications of the 22q11.2 region are reciprocal to the velocardiofacial syndrome (VCFS)/DiGeorge syndrome (DGS) recurrent deletions. The size of the duplications ranges from 1.5 to 3 megabases (Mb), depending upon the low copy repeats (LCRs) involved in the rearrangement. The LCRs surrounding the region are known as LCR22A to LCR22D. The common duplication is 3 Mb long and encompasses LCR22A to LCR22B. The common duplication includes T-box 1 (TBX1), the putative gene for the congenital heart defects seen in this condition. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '22q11.2 deletion syndromes (DiGeorge syndrome/velocardiofacial syndrome)'.)

The clinical features share some similarities with VCFS/DGS, including mild-to-severe intellectual disability (deficits of memory performance, perceptual organization, and verbal comprehension; attention deficit hyperactivity disorder [ADHD]; and speech impairment), growth restriction, velopharyngeal incompetence, heart defects, and palatal abnormalities. Heart defects reported share similarities with the deletion and include defects affecting the outflow ventricular tracts and other conotruncal abnormalities [79-81]. Other clinical findings reported include visual and hearing impairment, seizures, microcephaly, ptosis, and urogenital abnormalities. These duplications may also play a role in neuropsychiatric development, conferring protection against schizophrenia [82]. Losses of these regions are highly associated with schizophrenia. Studies suggest that this duplication is more common (1 in 700) and has a higher incidence of congenital anomalies involving congenital heart defects, growth difficulties, and vision problems than previously reported [83].

Many of these duplications are inherited, some of them from unaffected parents; therefore, caution should be applied in interpreting genetic testing results and counseling families appropriately given the interfamilial and intrafamilial clinical variability seen with this duplication [84,85].

Screening studies include formal developmental evaluation, echocardiogram, and swallowing evaluations. Patients may benefit from physical, occupational, and speech therapies.

22q13 DUPLICATIONS — Duplications of the 22q13 region have been reported in a few children with infantile hypotonia, mild-to-moderate developmental delay, microcephaly, autism spectrum disorder, growth deficiency, and mild dysmorphic facial features [86]. This region includes several genes associated with mitochondrial function, and one patient with 22q13 duplication has been reported with mitochondrial disease [87]. The critical region includes the Src homology 3 and multiple ankyrin repeat domains 3 (SHANK3) gene. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '22q13.3 deletion syndrome (Phelan-McDermid syndrome)'.)

SUMMARY

●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 those resulting from copy number gains (duplication syndromes). (See 'Overview of genomic disorders' above.)

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

●7q11.23 duplication syndrome (Williams-Beuren region duplication syndrome) – Deletions in the 7q11.23 region are associated with Williams syndrome (MIM #609757). The reciprocal duplication causes a different clinical phenotype characterized by hypotonia and global developmental delay, with speech delay that can range from moderate to severe. (See '7q11.23 duplication syndrome (Williams-Beuren region duplication syndrome)' above.)

●15a11-13 duplication syndrome – Gains and duplications of the 15q11-13 region are seen in some patients with autism (MIM #608636). These patients may also present with hypotonia, global developmental delay, attention deficit hyperactivity disorder (ADHD), ataxia, and seizures. (See '15q11-13 duplication syndrome' above.)

●17p11.2 duplication syndrome (Charcot-Marie-Tooth type 1A [CMT1A] disease) – Recurrent 1.5 megabase (Mb) duplications in 17p11.2 involving the peripheral myelin protein 22 (PMP22) gene are responsible for CMT1A disease (MIM #118220). CMT1A is a demyelinating motor-sensory neuropathy clinically characterized by progressive distal neuromuscular weakness. (See '17p11.2 duplication syndrome (Charcot-Marie-Tooth type 1A disease)' above.)

●22q11.2 duplication syndrome (velocardiofacial syndrome/DiGeorge syndrome) – Duplications of the 22q11.2 region are reciprocal to the velocardiofacial syndrome (VCFS)/DiGeorge syndrome (DGS) recurrent deletions. The clinical features share some similarities with VCFS/DGS, including mild-to-severe intellectual disability (deficits of memory performance, perceptual organization, and verbal comprehension; ADHD; and speech impairment), growth restriction, velopharyngeal incompetence, heart defects, and palatal abnormalities. Other clinical findings reported include visual and hearing impairment, seizures, microcephaly, ptosis, and urogenital abnormalities. (See '22q11.2 duplication syndrome' above.)