Clinical Diagnosis

16p11.2 microdeletion is characterized by:

• Delayed language development, with expressive language typically more affected than receptive language

• Learning difficulties/intellectual disability

• Social impairments with or without a diagnosis of autism spectrum disorder (ASD)

• Minor dysmorphic facial features without a consistent pattern

Most 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 Testing

Genes. 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 testing

Deletion/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

Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
Deletion/ duplication analysis 2 3	Deletion	~100% with appropriate probes 4	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

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 Strategy

Establishing 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).

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

16p11.2 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.

Natural History

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].

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 85-95^th centile) and obesity (defined as sex-specific BMI for age >95^th 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].

Genotype-Phenotype Correlations

Most individuals have the same size 16p11.2 microdeletion at the approximate chromosome position of 29.5-30.1 Mb in the reference genome (NCBI Build 36.1; hg18).

Penetrance

16p11.2 microdeletion is recently described and accurate data that allow calculation of penetrance are not yet available. Although initial reports suggested that 16p11.2 microdeletion is highly penetrant, this may have been an overestimate resulting from ascertainment bias for developmental delay, intellectual disability, or ASD, because subsequent reports suggest that penetrance may be reduced. Weiss et al [2008] reported 16p11.2 microdeletion in three controls who participated in a study of bipolar disorder but were not screened for autism and in two controls from a different study in which controls were not screened for a psychiatric or language disorder.

Bijlsma et al [2009] and Hanson et al [2010] reported normal cognitive functioning for some individuals with 16p11.2 microdeletion.

Glessner et al [2009] reported equal frequency of 16p11.2 microdeletion among persons with autism and controls, but other studies have consistently reported an increased frequency of 16p11.2 microdeletion among individuals with autism as compared to controls.

Variable expressivity has been observed for the degree of cognitive impairment and for the presence of ASD and other neuropsychiatric disorders. This variability is similar to that observed for other well-known microdeletion syndromes such as 22q11.2 deletion syndrome.

Anticipation

To date, anticipation has not been observed. In cases of inherited microdeletion, parental break points appear similar to the proband at the level of resolution of oligonucleotide aGH.

Nomenclature

Owing to the lack of distinguishing physical examination features in persons with a 16p11.2 microdeletion, the phenotype associated with the microdeletion has not been described eponymously. Although the 16p11.2 region includes many segmental duplication break points [Ballif et al 2007], the 16p11.2 microdeletion specifically refers to the region at chromosomal coordinates 29.5 Mb to 30.1 Mb.

Prevalence

Estimates of prevalence vary. In one population of 299 individuals with autism and 18,834 control samples, three individuals in each category had 16p11.2 microdeletion, giving a population prevalence of approximately 3:10,000 [Weiss et al 2008]. It should be noted that “controls” in that study may have had other diagnoses besides autism. Thus, some degree of neurodevelopmental disability in those individuals cannot be ruled out.

A summary of the available literature suggested that the frequency of 16p11.2 microdeletion could exceed 1:5,000 and is found in approximately 0.5% of all samples tested clinically [Rosenfeld et al 2010]. Based on unpublished information, the 16p11.2 microdeletion is observed in approximately one of every 300 samples submitted for clinical aGH testing, similar to the 0.5% estimate. Clinical testing typically includes individuals with developmental delay, intellectual disability, or ASD as the most common diagnostic categories.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with 16p11.2 microdeletion, the following are recommended:

• Measurement of height and weight

• Broad review of all organ systems

• Routine clinical examination, including dysmorphology examination

• Developmental assessment with cognitive and behavioral testing

• Consider consultation with a neurologist and EEG testing if history suggests the possibility of seizures

• In patients with spinal curvature, diagnostic radiographs of the spine

• Consider evaluation and echocardiogram by a cardiologist

• Screening for hypertension and diabetes in patients who are overweight or obese

Treatment of Manifestations

Manifestations 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.

Surveillance

Routine 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

16p11.2 microdeletion is a contiguous deletion. In many cases, the proband has a de novo deletion. Although the association of this microdeletion with cognitive impairment and features of autism and the relatively high rate of de novo cases suggest a lowering of reproductive fitness, clear instances of parent-child transmission have been observed. Inherited microdeletions are transmitted in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most reported probands have a de novo microdeletion of 16p11.2.

• If inherited, the microdeletion has not been reported to have a parent-of-origin bias.

• Recommendations for the evaluation of parents of a proband include MLPA or FISH testing because mildly affected and unaffected individuals have been identified with 16p11.2 microdeletion. Although it has not been described for 16p11.2 microdeletions per se, normal parents of an affected proband could have somatic mosaicism.

• Weiss et al [2008] and Kumar et al [2008] both reported at least one instance of presumed germline mosaicism in a multiplex family in which sibs who were not monozygous twins both had 16p11.2 microdeletion presumed to be de novo.

Sibs of a proband

• The risk to the sibs of a proband depends on the deletion status of the parents.

• If the parents of an individual with 16p11.2 microdeletion syndrome have normal MLPA or FISH studies, the risk to sibs is low but greater than that of the general population because a parent may have germline mosaicism or low-level somatic mosaicism for the microdeletion.

• If a parent also has the 16p11.2 microdeletion, the risk to each sib is 50%.

Offspring of a proband. Offspring of individuals with the 16p11.2 microdeletion have a 50% chance of inheriting the deletion.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent has the 16p11.2 microdeletion, his or her family members may also have the deletion.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 16p11.2 microdeletion.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using interphase FISH in the same manner described in Molecular Genetic Testing. However, it is not possible to reliably predict the phenotype from a laboratory finding of 16p11.2 microdeletion.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the diagnosis of 16p11.2 microdeletion has been established in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

16p11.2 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.

Published Guidelines/Consensus Statements

1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available at www.ashg.org. 1995. Accessed 2-3-11.
2. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2006 Principal Investigators, Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, United States, 2006. Available at www.cdc.gov. 2009. Accessed 2-3-11.
3. Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics, Bright Futures Steering Committee, Medical Home Initiatives for Children with Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Available at pediatrics.aappublications.org. Subscription or institutional access required. 2006. Accessed 2-3-11.
4. Johnson CP, Myers SM, American Academy of Pediatrics Council on Children With Disabilities (2007) Identification and evaluation of children with autism spectrum disorders. Available at pediatrics.aappublications.org. Subscription or institutional access required. 2007. Accessed 2-3-11.
5. Myers SM, Johnson CP; American Academy of Pediatrics Council on Children With Disabilities. Management of children with autism spectrum disorders. Available at pediatrics.aappublications.org. Subscription or institutional access required. 2007. Accessed 2-3-11.

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Author History

Ellen Hanson, PhD (2009-present)
Rachel Hundley, PhD; Children’s Hospital Boston (2009-2011)
David T Miller, MD, PhD, FACMG (2009-present)
Ramzi Nasir, MD, MPH (2009-present)
Yiping Shen, PhD, FACMG (2009-present)
Magdi M Sobeih, MD, PhD (2009-present)
Bai-Lin Wu, MMed, PhD, FACMG (2009-present)

Revision History

• 27 October 2011 (dtm) Revision: author addition to Evaluations Following Initial Diagnosis

• 8 February 2011 (me) Comprehensive update posted live

• 22 September 2009 (et) Review posted live

• 6 March 2009 (dtm) Original submission