Hernando et al. (2002) reported the first case of multiple congenital anomalies associated with a de novo interstitial deletion of band 16p11.2 confirmed by array comparative genomic hybridization (CGH). Ultrasound examination at age 20 weeks' gestation showed cardiac ... Hernando et al. (2002) reported the first case of multiple congenital anomalies associated with a de novo interstitial deletion of band 16p11.2 confirmed by array comparative genomic hybridization (CGH). Ultrasound examination at age 20 weeks' gestation showed cardiac defects and unilateral multiple renal cysts. At birth, the male infant showed severe intrauterine growth retardation and dysmorphic features, including flat facies, microretrognathia, blepharophimosis, short nose with hypoplastic nasal alae and absent nasal bridge, low-set and malformed ears, coloboma, and unilateral chorioretinitis. Other features included tetralogy of Fallot with pulmonary atresia, cubital deviation of the hands, talipes varus, articular limitation, and hemivertebra at level L1. He also had unilateral renal agenesis and cryptorchidism. The deletion occurred on the maternally derived chromosome. He died of cardiac failure at age 5 months. Shimojima et al. (2009) reported a 3-year-old boy with intrauterine growth retardation who had developmental delay, multiple hemivertebrae, missing ribs, inguinal hernia, and hydrocele testis. He could stand without support, but was unable to communicate verbally and showed hyperactivity, but did not fulfill the criteria for autism. He had mild dysmorphic features with microcephaly, bilateral ptosis, and a long nose. Brain MRI showed mild dilatation of the lateral ventricles. Array CGH identified an interstitial 593-kb deletion on chromosome 16p11.2 between homologous segmental duplications. The deletion was identical to the common deletion previously identified in patients with autism spectrum disorder (Weiss et al., 2008; AUTS14; see CYTOGENETICS). The mother also carried the deletion and was suspected to be borderline mentally retarded, but did not have autism and was not formally tested. Shimojima et al. (2009) noted that the patient reported by Hernando et al. (2002) also had hemivertebrae, and postulated involvement of the TBX6 gene (602427). Shinawi et al. (2010) identified 27 individuals with a 16p11.2 deletion and 18 with a 16p11.2 duplication, accounting for 0.6% of 7,400 samples submitted for testing, most commonly for developmental delay and mental retardation. Sixteen patients with deletions were examined in detail. The deletion was confirmed to be de novo in 8 of 10 families, and was inherited from an affected father or an asymptomatic healthy parent in 1 family each. Deletions or duplications within this region were not observed in 194 normal parental samples. Although neither group constituted a clearly clinically recognizable syndromes, there were some common phenotypic features. All probands showed speech/language delay and cognitive impairment. Those with deletions had macrocephaly, broad forehead, micrognathia, hypertelorism, and a flat midface. Deletion carriers had motor delay (50%), seizures (40%), and congenital anomalies (30%). Only 3 of 16 patients with the 16p11.2 deletion met criteria for autism, and only 2 with duplications had autistic features. However, patients from both groups had an increased incidence of other behavioral problems, most commonly attention-deficit hyperactivity disorder. All the deletions and duplications appeared to be recurrent and reciprocal, with a minimum size of 579 kb. Breakpoint analysis identified 2 major families of low copy repeat (LCR) regions, 147 kb and 72 kb repeats, respectively, that contributed to the genomic complexity in this region. Shinawi et al. (2010) emphasized the incomplete penetrance and variable expressivity of clinical findings in patients with these genomic abnormalities. Fernandez et al. (2010) reported 5 autistic probands with copy number variation (CNV) at 16p11.2, including 3 with deletions and 2 with duplications, and 1 proband with duplication and developmental delay and autistic-like features. Two of the 3 probands with deletions had notable dysmorphic features. The first proband was a 13-year-old boy with low nuchal hairline, short neck, flat face, low-set ears, narrow palpebral fissures, short nose with flat broad nasal root, smooth philtrum, widely spaced upper incisors, and pointed chin. He also had small hands with distally tapered fingers, short toes, micropenis, and obesity. He carried a de novo deletion. His sister, who did not carry the deletion, had Asperger syndrome and was not dysmorphic. The second proband was an 18-year-old girl who did not have dysmorphic features. Her deletion was also de novo, and she had a younger brother without the deletion who had autism. The third proband with a deletion inherited it from his affected mother. He had tall broad forehead with hypertelorism, midface hypoplasia, anteverted nares, smooth philtrum, wide mouth, and posteriorly rotated ears. His brother also carried the deletion and had similar facial features and autism. Their mother, who had mild mental retardation and autism, was brachycephalic with a receding hairline, deep-set eyes, smooth philtrum, large ears, and unusually short fifth toes. Fernandez et al. (2010) noted the extensive phenotypic variability in these patients, as some deletion-positive ASD probands had less severe phenotypes as deletion-negative ASD sibs. Compared with the microduplications, the microdeletions were more likely to be penetrant and to be associated with nonspecific major or minor dysmorphism. The results also indicated incomplete penetrance and supported the concept that sex difference provides a relative advantage in protecting females against the development of ASD even when a rare CNV is present. Wat et al. (2011) reported 2 unrelated patients with multiple congenital anomalies, but ascertained due to congenital diaphragmatic hernia (CDH), who each had a de novo interstitial deletion of 16p11.2. A 2-year-old boy with right-sided CDH, microretrognathia, cleft palate, right inguinal hernia, and paternally inherited autosomal dominant polydactyly had biallelic 554-kb and 982-kb deletions of chromosome 16p11.2 by real-time quantitative PCR. The other patient was a newborn infant with left-sided CDH, hypoplastic nonarticulating thumbs, extrathoracic vertebra, and 13 pairs of ribs, who died on the 17th day of life with severe respiratory insufficiency and pulmonary hypertension. He was found to have a 771-kb deletion by FISH analysis. Schaaf et al. (2011) reported 2 unrelated boys with heterozygous deletions of 16p11.2 and a third boy with a duplication of this region. The deletion patients had language delay and learning disabilities, and 1 met criteria for pervasive developmental disorder. Both deletion patients had symptomatic long cervicothoracic syringomyelia, 1 associated with Chiari I malformation and cerebellar tonsillar herniation, and the duplication patient had symptomatic long thoracolumbar syringomyelia. One of the deletion patients was obese. The minimal size of the rearrangement in all 3 patients was 579 kb. - Clinical Variability Shiow et al. (2009) reported a girl with attention deficit-hyperactivity disorder and mild cognitive impairment associated with a de novo heterozygous 600-kb deletion of chromosome 16p11.2 encompassing 24 genes, including CORO1A (605000). In addition, she had T-, B+, NK+ severe combined immunodeficiency (SCID) characterized by early-onset recurrent infections and post-vaccination varicella at age 13 months. Immunologic workup showed decreased numbers of lymphocytes, poor T-cell function with decreased proliferative response and lack of helper T-cell function for antibody isotype switching, and low immunoglobulins. Her thymus was present. Hematopoietic stem cell transplantation was successful. Molecular studies excluded mutations in known SCID genes and identified a heterozygous 2-bp deletion in the CORO1A gene (605000.0001) that was inherited from the unaffected father. Thus, she had a homozygous absence of the CORO1A gene, with absent expression of the protein in her lymphocytes. Shiow et al. (2008) demonstrated that Coro1a is mutated in a mouse model with a peripheral T cell deficiency (Ptcd), providing further evidence for pathogenicity. - Association of the 593-kb Deletion Region with Obesity Bochukova et al. (2010) noted that 4 patients carrying 750- to 780-kb deletions of chromosome 16p11.2, which included the 593-kb region, had developmental delay and/or autism and severe obesity and had been previously reported by Kumar et al. (2008), Weiss et al. (2008), or Marshall et al. (2008). Walters et al. (2010) reported a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kb at chromosome 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from 8 European cohorts. These deletions were absent from healthy nonobese controls and accounted for 0.7% of morbid obesity cases (body mass index (BMI) greater than or equal to 40 kg/m(2), or BMI standard deviation score greater than or equal to 4.0; p = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with a strong effect.
DiagnosisClinical Diagnosis16p11.2 microdeletion is characterized by:Delayed language development, with expressive language typically more affected than receptive languageLearning difficulties/intellectual disabilitySocial impairments with or without a diagnosis of autism spectrum disorder (ASD)Minor dysmorphic facial features without a consistent patternMost individuals with 16p11.2 microdeletion are identified by array genomic hybridization (aGH) performed in the context of developmental delay, intellectual disability, or ASD. Note: Prior to 2008 many aGH platforms did not include coverage for this region.Note: (1) For this GeneReview, 16p11.2 microdeletion is defined as the presence of a common ~550-kb deletion at the approximate position of 29.5-30.1 Mb in the reference genome (NCBI Build 36.1; hg18). (2) This region of chromosome 16p contains segmental duplications in addition to the ones flanking this 550-kb region, and larger deletions involving this region occur, including one report of an individual with an 8.7-Mb deletion overlapping the 16p11.2 550-kb region and extending to 16p12.2 (position ~21.4 Mb to 30.1 Mb by NCBI Build 36.1; hg18). This patient exhibited intellectual disability, dysmorphic features including cleft lip and palate, hand anomalies, and unexplained syncope [Ballif et al 2007]. These additional segmental duplication break points, spanning 16p11.2 to 16p12.2, are well described by Ballif et al [2007].Routine G-banded karyotyping does not detect 16p11.2 deletion.Molecular Genetic TestingGenes. 16p11.2 recurrent microdeletion involves the loss of one chromosomal segment harboring 25 annotated genes or transcripts [Kumar et al 2008, Marshall et al 2008, Weiss et al 2008]. The recurrent deletion is flanked by segmental duplications that contain three additional genes. It is unknown how deletion of any of the 25 genes causes the clinical findings of 16p11.2 microdeletion. Clinical testingDeletion/duplication analysis. A variety of methods may be used, including:Array genomic hybridization (aGH). 16p11.2 recurrent deletions are detectable by current clinical oligonucleotide aGH platforms, and some bacterial artificial chromosome (BAC)-based platforms. Note: (1) 16p11.2 microdeletion may not be detectable by older oligonucleotide or BAC platforms, and may not be detectable by some platforms still in use in some labs (e.g., BAC platforms with 1-Mb spacing). (2) The ability to size the deletion and the need for independent confirmation depends on the type of array used and the density of probes. Oligonucleotide aGH or quantitative polymerase chain reaction (qPCR) are likely the best methods for determining the exact size of the 16p11.2 microdeletion.Multiplex ligation-dependent probe amplification (MLPA) can detect microdeletions of 16p11.2 [Weiss et al 2008]. MLPA is a quantitative multiplex PCR approach for determining relative copy number of a genomic target sequence. Note: Whether or not it is possible to size the deletion depends on the number and distribution of MLPA probes in the 16p11.2 region.FISH. Metaphase FISH can detect the deletion. Note: (1) The 16p11.2 microdeletion is not detectable by G-banded karyotype. (2) Routine FISH methods cannot size the deletion. Quantitative PCR (qPCR) is an alternative to MLPA for determining relative copy number of a genomic target sequence. Note: FISH, MLPA, and/or qPCR can be used for initial detection of the deletion and are often used as confirmation of aGH findings. In addition, these methods may be used to test relatives of a proband known to have a deletion.Research testing. Sequencing of genes in the 16p11.2 genomic region is being pursued as a research study. Currently, no reported genes in this region harbor mutations that are definitively associated with developmental delay or autism.Table 1. Summary of Molecular Genetic Testing Used in 16p11.2 Microdeletion View in own windowTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityDeletion / duplication analysis 2 3Deletion~100% with appropriate probes 4Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.3. FISH, MLPA, and/or qPCR can be used for initial detection of the deletion and are often used as confirmation of aGH findings. In addition, these methods may be used to test relatives of a proband known to have a deletion.4. Extent of deletion detected may vary by method and by laboratory.Testing StrategyEstablishing the diagnosis in a proband requires detection of the common ~550-kb deletion at 16p11.2.Evaluating at-risk relatives. MLPA, FISH, or qPCR can be used to identify 16p11.2 deletion in relatives of the proband.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deletion in the proband. Whether prenatal diagnosis or PGD for 16p11.2 microdeletion is appropriate clinically is uncertain given the inherent difficulty in predicting the phenotype accurately (see Prenatal Testing).Genetically Related (Allelic) Disorders16p11.2 microduplication. Reciprocal ~550-kb duplication of 16p11.2 has been reported in individuals with developmental delays and/or ASD [Kumar et al 2008, Marshall et al 2008, Weiss et al 2008]. In the study by Weiss et al [2008], 16p11.2 microduplication was found in two control individuals with bipolar disorder. The reciprocal duplication has also been reported in at least two cases of childhood-onset schizophrenia [Walsh et al 2008]. Microduplication of 16p11.2 has been shown to confer an increased risk for schizophrenia in two large cohorts [McCarthy et al 2009]. The microduplication was associated with a 14.5-fold increased risk of schizophrenia whereas the reciprocal microdeletion was associated with autism and developmental disorders.The clinical significance of 16p11.2 microduplication is less clear than the significance of 16p11.2 microdeletion. Most individuals with 16p11.2 microduplications are identified by aGH performed in the context of developmental delay, intellectual disability, or ASD. This ascertainment bias makes the phenotype associated with 16p11.2 microduplication difficult to establish. Persons with 16p11.2 microduplication do not have characteristic dysmorphic features that would facilitate a clinical diagnosis. Whereas 16p11.2 microdeletions are often de novo, a larger proportion of microduplications are inherited. Parents with a 16p11.2 microduplication may not have a history of developmental delay, ASD, or other neurodevelopmental symptoms. More investigation is needed to determine if the reciprocal 16p11.2 microduplication is a normal copy number variant or a low penetrance risk factor for developmental delay, ASD, and/or psychiatric disorders.Note: (1) 16p11.2 recurrent microduplications are detectable by the same methods that detect the 16p11.2 microdeletion (see Molecular Genetic Testing). (2) 16p11.2 microdeletion and the reciprocal microduplication are not detectable by G-banded karyotype. (3) Routine metaphase FISH analysis cannot detect microduplication of 16p11.2 because duplication (or greater intensity of the signal) cannot be recognized. Thus, a normal metaphase FISH study does not exclude 16p11.2 microduplication. (4) Interphase FISH can detect the microduplication. 16p11.2-p12.2 microdeletion. 16p11.2-p12.2 microdeletion involving more significant congenital anomalies and dysmorphic features than 16p11.2 microdeletion has been described [Ballif et al 2007] with a suggested smallest region of overlap (SRO) extending from position ~21.3 Mb to ~28.5 Mb on chromosome 16 (NCBI Build 36.1; hg18). Another individual with an overlapping 8.2-Mb deletion (position ~21.3 Mb to ~29.5 Mb by NCBI Build 36.1; hg18) had moderate intellectual disability, dysmorphic features, severely delayed speech development, and hyperactivity with short attention span, but not autism [Battaglia et al 2009]. This larger microdeletion does not typically involve the smaller but much more common ~550-kb recurrent microdeletion at position ~29.5 Mb to ~30.1 Mb discussed in this GeneReview.16p11.2 microdeletion of ~200kb [29.7-29.9Mb; hg18]. This small microdeletion is located distal to the typical 16p11.2 microdeletion and has been reported as a predisposing factor for overweight and obesity, as discussed in Clinical Description. Autosomal dominant paroxysmal kinesigenic dyskinesia. A form of autosomal dominant paroxysmal kinesigenic dyskinesia has been mapped to 16p11.2-q13 [Tomita et al 1999, Bennett et al 2000]. Onset of movement-induced dyskinesias or choreoathetosis begins in the latter part of the first or second decade of life with increasing frequency of paroxysms with age. Numerous candidate genes have been identified, but to date none has demonstrated mutations in the affected individuals [Kikuchi et al 2007, Du et al 2008]. The dyskinesia is responsive to low doses of antiepileptic medications such as carbamazepine.
16p11.2 microdeletion was first reported as a recurrent microdeletion in individuals with ASD [Kumar et al 2008, Marshall et al 2008, Weiss et al 2008]. Prior to that, the same 16p11.2 microdeletion was reported as a de novo copy number variant in an individual with Asperger disorder [Sebat et al 2007] and in two monozygotic twins with seizures, mild intellectual disability, and aortic valve abnormalities [Ghebranious et al 2007]....
Natural History16p11.2 microdeletion was first reported as a recurrent microdeletion in individuals with ASD [Kumar et al 2008, Marshall et al 2008, Weiss et al 2008]. Prior to that, the same 16p11.2 microdeletion was reported as a de novo copy number variant in an individual with Asperger disorder [Sebat et al 2007] and in two monozygotic twins with seizures, mild intellectual disability, and aortic valve abnormalities [Ghebranious et al 2007].Males and females are equally affected. No long-term clinical follow-up data are available. Developmental delay. Most, if not all, known individuals with 16p11.2 microdeletion experience some degree of developmental delay, although the severity varies. In the authors’ clinical experience, most individuals with a 16p11.2 microdeletion have been ascertained through genetic testing performed in the context of developmental delay, intellectual disability, or ASD. Developmental delays in this population are more related to diminished language and cognitive function than to motor disability.Cognitive impairment. Individuals with 16p11.2 microdeletion exhibit IQ scores ranging from mild intellectual disability to normal [Hanson et al 2010]. Individuals with IQ scores in the average range frequently have some other form of developmental issues such as language delay or ASD.Language delay. Expressive language appears to be more affected than receptive language. Hanson et al [2010] reported that nine verbal individuals with 16p11.2 microdeletion exhibited language delay: six acquired single words at a delayed rate (at or after age 24 months, mean age 30 months); seven acquired phrases at or after age 33 months (mean age 41 months); and all had current deficits in reciprocal conversation. It is speculated that these delays in language development may contribute to behavior problems.Autistic features. Individuals with 16p11.2 microdeletion identified in the earliest reported research studies were ascertained primarily through cohorts of individuals with autism spectrum disorders (ASDs). Not all individuals with 16p11.2 microdeletion have a diagnosis of ASD, as described in research studies that include individuals with other neurodevelopmental disabilities [Weiss et al 2008]. Weiss et al [2008] proposed that this deletion does not involve 100% penetrance for a strictly defined form of autism, but represents a highly penetrant cause of developmental disability. 16p11.2 microdeletion was identified in seven of 1,105 children (0.7%) with unexplained intellectual disability but no history of autism [Mefford et al 2009]. Similar genetic testing of 4,284 individuals with intellectual disability or multiple congenital anomalies detected 22 (14 index cases and 8 family members) with microdeletions of 16p11.2 [Bijlsma et al 2009]. Individuals identified in these reports did not have a recognizable clinical phenotype. In a study by Hanson et al [2010] 11 individuals with 16p11.2 microdeletion were evaluated for ASD using detailed phenotyping measures including the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview. Three (27%) met full criteria for ASD (i.e., cutoffs on both measures); six (55%) had findings of ASD but did not meet full criteria; and two (18%) did not meet criteria for ASD. In addition, all 11 had some level of restricted or repetitive behavior patterns or interests either currently or in the past [Gault et al 2003]. Based on current literature reports, ASD is not diagnosed in most individuals with 16p11.2 microdeletion, but still is much more common than in the general population, in which ASD is diagnosed in approximately one in 150 children.Dysmorphic features. Persons with 16p11.2 microdeletion do not have a characteristic pattern of dysmorphic features that would facilitate a clinical diagnosis. However, several studies have reported on various dysmorphic features [Shinawi et al 2010, Bijlsma et al 2009, Rosenfeld et al 2010].Neurologic issues. Individuals with 16p11.2 microdeletion appear to be at higher than average risk for seizures, or EEG abnormalities without overt seizures, based on a few retrospective clinical reports in which seizures were identified in three of 14 individuals [Bijlsma et al 2009], two of 18 [Rosenfeld et al 2010], and five of 16 [Shinawi et al 2010]. Hypotonia has been noted in a minority of individuals with 16p11.2 microdeletion [Rosenfeld et al 2010]. Otherwise, individuals with 16p11.2 microdeletion do not appear to be at higher than average risk for other severe neurologic disorders. Brain MRI findings, reported in a few studies, include findings such as arachnoid cyst [Bijlsma et al 2009] and prominent ventricles [Shinawi et al 2010]. Most persons with 16p11.2 microdeletion were reported to have normal MRI findings. In the authors’ unpublished clinical experience, a minority of individuals with 16p11.2 microdeletion have nonspecific MRI findings of unclear clinical significance. At this time, no clear evidence suggests that the types of issues identified on MRI would affect clinical management.Obesity. Microdeletion of 16p11.2 appears to be a predisposing factor for overweight (defined as sex-specific BMI for age 85-95th centile) and obesity (defined as sex-specific BMI for age >95th centile).Early clinical reports on 16p11.2 microdeletion suggested a possible association with overweight [Ghebranious et al 2007, Shinawi et al 2010, Bijlsma et al 2009, Fernandez et al 2010]. Subsequently, two studies designed to identify genetic predisposing factors in individuals ascertained for obesity rather than for autism or developmental delay reported that microdeletions at 16p11.2 (29.5-30.1 Mb; hg18) cosegregated with obesity [Bochukova et al 2010, Walters et al 2010]. A smaller, ~200-kb (28.7-28.9 Mb; hg18) microdeletion adjacent to the typical 16p11.2 microdeletion that also cosegregated with obesity in three individuals was inherited from an obese parent in all three [Bochukova et al 2010]. Association of this ~200-kb microdeletion with obesity was confirmed in a separate study of 31 individuals with the same small microdeletion. Both studies commented that the ~200-kb region includes SH2B1, the gene known to be involved in leptin and insulin signaling.Overall, these studies show that the prevalence of overweight and obesity in individuals with 16p11.2 microdeletion is higher than in the general population. Longitudinal follow-up studies will be necessary in order to understand the trajectory of body mass gain associated with 16p11.2 microdeletion and the effectiveness of body mass management schemes. Since most of the individuals identified with 16p11.2 microdeletion are young, the long-term consequences of obesity among these individuals are currently unknown. However, it seems that they are likely to suffer the same consequences as other young individuals with early-onset obesity. Psychiatric disease. Weiss et al [2008] reported an increased frequency of 16p11.2 microdeletion among individuals with a psychiatric or language disorder as compared to controls, including one of 648 persons with schizophrenia, one of 420 persons with bipolar disorder, one of 203 persons with ADHD, and one of 3,000 persons with panic disorder. Hanson et al [2010] did not find a similar link to ADHD although symptoms of affective problems, somatic issues, and anxiety were commonly reported. These data suggest that 16p11.2 microdeletion may contribute to psychiatric disease; however, further study is required.Cardiac malformations and disease associations. Most individuals in whom the diagnosis of 16p11.2 microdeletion is suspected or confirmed have not had diagnostic cardiac imaging; however, limited clinical reports suggest that the incidence of relatively minor cardiac malformations may be increased. A report of twins with 16p11.2 microdeletion noted intellectual disability, seizures, and an aortic valve abnormality [Ghebranious et al 2007]. Those authors speculated on a possible role for the gene HIRIP3, located in the 16p11.2 microdeletion, as a regulator of aortic valve development. One retrospective analysis found an abnormal aorta and/or aortic valve in three of 18 individuals (16.7%). Another retrospective study of 16 individuals reported a patent foramen ovale (PFO) in two [Shinawi et al 2010].More recently, 16p11.2 microdeletion was identified in an infant who died in the newborn period from endocardial fibroelastosis [Puvabanditsin et al 2010]. Since this is a single case report, it should not be assumed that the 16p11.2 microdeletion was causative unless further cases are identified. Other medical issues. Persons with 16p11.2 microdeletion do not appear to have a consistent pattern of other medical problems. Height does not appear to be affected. Two separate case reports identified hemivertebrae in an individual with 16p11.2 microdeletion [Fernandez et al 2010, Shimojima et al 2009]. However, three large retrospective clinical reports encompassing almost 50 persons did not report hemivertebrae [Shinawi et al 2010, Bijlsma et al 2009, Rosenfeld et al 2010]. Also, a report of hemivertebrae and other anomalies in an individual with deletion of the entire 16p11.2 cytogenetic band [Hernando et al 2002] should not be considered as supporting a role for the typical 16p11.2 microdeletion in abnormal vertebral body formation. In another case report, two persons identified with 16p11.2 microdeletion and one with microduplication were reported to have syringomyelia. In one of the individuals with microdeletion, the syringomyelia was associated with a Chiari I malformation [Schaaf et al 2011].Individuals with 16p11.2 microdeletion do not generally have immunodeficiency. However, severe combined immunodeficiency (SCID) was reported in one individual with 16p11.2 microdeletion on one chromosome and a point mutation in CORO1A on the other chromosome [Shiow et al 2009].
The differential diagnosis is broad, including any cause of developmental delay and/or ASD without obvious distinguishing clinical features. This point underscores the importance of genetic testing in this patient population. ...
Differential Diagnosis The differential diagnosis is broad, including any cause of developmental delay and/or ASD without obvious distinguishing clinical features. This point underscores the importance of genetic testing in this patient population. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with 16p11.2 microdeletion, the following are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with 16p11.2 microdeletion, the following are recommended:Measurement of height and weightBroad review of all organ systemsRoutine clinical examination, including dysmorphology examination Developmental assessment with cognitive and behavioral testingConsider consultation with a neurologist and EEG testing if history suggests the possibility of seizuresIn patients with spinal curvature, diagnostic radiographs of the spineConsider evaluation and echocardiogram by a cardiologist Screening for hypertension and diabetes in patients who are overweight or obeseTreatment of ManifestationsManifestations of 16p11.2 microdeletion can be variable, and treatment should be targeted to the specific deficits identified. Early diagnosis and provision of therapies facilitate the best outcome. Referral to other appropriate medical specialists is recommended based on specific symptoms or signs. Specialists may include a developmental/behavioral pediatrician, pediatric neurologist, and/or medical geneticist.Due to the high incidence of neurodevelopmental disability, immediate referral to a clinical psychologist for full neuropsychological and/or developmental assessment for diagnostic differential and treatment recommendations is strongly suggested. Interventions may include speech and language therapy, occupational therapy, and physical therapy. Because of the high incidence of expressive language delays, speech therapy and augmentative and assistive means of communication should be considered early. Behavioral, social, and educational interventions for individuals with neurodevelopmental disabilities, including ASD, are also appropriate. Guidelines for management of individuals with ASD are available from the American Academy of Pediatrics [Myers et al 2007]. See .Weight management and nutrition counseling are an important part of clinical care for patients with 16p11.2 microdeletion. Brain and spine MRI should be considered especially if there are symptoms suggestive of a Chiari I malformation and/or spinal cord dysfunction.Persons with 16p11.2 microdeletion and a history of frequent infections should be tested for this form of severe combined immunodeficiency (SCID) by flow cytometry. SurveillanceRoutine developmental surveillance and screening are recommended because of the increased incidence of developmental delay, intellectual disability, and autism. These clinical diagnoses place individuals with 16p11.2 microdeletion at increased risk for developmental and mental health difficulties. The American Academy of Pediatrics has published guidelines on surveillance and screening to identify patients with developmental disorders in general [Council on Children with Disabilities et al 2006] and autism in particular [Johnson et al 2007] and recommendations for management of children with ASD [Myers et al 2007]. See Published Guidelines/Consensus Statements.Periodic reevaluation by a medical geneticist can apprise the family of new developments and/or recommendations and facilitates long-term monitoring for emerging medical or mental health concerns.Based on reports of vertebral anomalies in a few individuals, clinical screening for scoliosis is recommended until the age of skeletal maturity.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. 16p11.2 Microdeletion: Genes and DatabasesView in own windowCritical RegionGene SymbolChromosomal LocusProtein NameAUTS14 Not applicable16p11.2Not applicableData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for 16p11.2 Microdeletion (View All in OMIM) View in own window 611913CHROMOSOME 16p11.2 DELETION SYNDROME, 593-KBMolecular Genetic Pathogenesis16p11.2 microdeletion is mediated by recombination between flanking 147-kb low-copy repeat sequences with 99.5% sequence identity [Ghebranious et al 2007, Sebat et al 2007, Kumar et al 2008, Marshall et al 2008, Weiss et al 2008]. The reciprocal duplication is also mediated by recombination at the same site. The 16p11.2 recurrent microdeletion involves the loss of one chromosomal segment harboring 25 annotated genes or transcripts [Weiss et al 2008]. How deletion of these genes results in the clinical symptoms of the syndrome is unknown, but ongoing investigations may identify one or more genes as responsible for the phenotypic features. Initial attempts at identifying causative genes have included association studies and resequencing of genes in the 16p11.2 region. Data from genome-wide association studies (GWAS) based on individuals with autism spectrum disorders and their family members have not identified any common variants associated with autism [Kumar et al 2009]. Resequencing of coding and promoter regions for eight candidate genes within the 16p11.2 region (ALDOA, DOC2A, HIRIP3, MAPK3, MAZ, PPP4C, SEZ6L2, TAOK2) selected based on their known expression patterns and functions was performed on approximately 100 individuals with autism. In total, 26 novel variants were identified: 13 exonic (9 nonsynonymous, 3 synonymous, and 1 untranslated region) and 13 promoter variants. A coding variant in the seizure-related gene SEZ6L2 was associated with autism in this sample (12/1106 autism vs. 3/1161 controls; p = 0.018). Further studies are required to determine if these results can be replicated.