16p11.2 Recurrent Microdeletion

Clinical characteristics.

The 16p11.2 recurrent microdeletion phenotype is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder (ASD). Developmental delays are related to diminished language, cognitive function, and motor impairments. While IQ scores range from mild intellectual disability to normal, those with IQ scores in the average range typically have other developmental issues such as language delay or ASD. Expressive language appears to be more affected than receptive language. Seizures are observed in approximately 20% of individuals with the recurrent microdeletion. Macrocephaly is common, usually becoming apparent by age two years. Chiari malformations/cerebellar ectopia are the most frequently observed structural brain abnormalities. In individuals with the 16p11.2 recurrent microdeletion the frequency of birth defects of all types is slightly increased, with vertebral anomalies appearing to be most frequent.

Diagnosis/testing.

The 16p11.2 microdeletion is defined as the recurrent ~593-kb heterozygous deletion at the approximate position of 29.6-30.2 Mb in the reference genome (GRCh37/hg19). The microdeletion is identified by genomic testing that determines copy number of sequences, such as chromosomal microarray (CMA). This deletion cannot be detected by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques. While FISH analysis is not appropriate for identification of the deletion in a proband, it may be used to test relatives of a proband who is known to have the deletion.

Management.

Treatment of manifestations: Treatment should be targeted to the specific deficits identified. Full developmental assessment, including neuropsychological testing by a clinical psychologist, is strongly suggested to establish neurodevelopmental needs and treatment recommendations. Refer to a neurologist if seizures are suspected. Because of the high risk of obesity beginning in adolescence, encourage healthy eating habits with attention to portion size and an active lifestyle from a young age. Routine management of vertebral anomalies.

Surveillance: Routine surveillance, screening, and management based on American Academy of Pediatrics published guidelines on developmental delays and ASD. Maintain a low index of suspicion for possible seizures (which may manifest as, e.g., abnormal movements, staring spells). Obtain brain MRI if manifestations of Chiari I malformation appear. Periodic reevaluation by a medical geneticist to apprise the family of new developments and/or recommendations and facilitate long-term monitoring for emerging medical and/or mental health concerns.

Genetic counseling.

16p11.2 microdeletion is inherited in an autosomal dominant manner. The proband often has a de novo deletion; however, the deletion can also be transmitted from a parent to a child. Prenatal diagnosis for at-risk pregnancies requires prior identification of the deletion in an affected family member. Interpretation of results from prenatal testing is challenging given the inherent difficulty in accurately predicting the phenotype.

Suggestive Findings

The 16p11.2 recurrent microdeletion should be suspected in individuals with the following clinical findings:

• Delayed language development (with expressive language typically more affected than receptive language) and abnormal speech articulation
• Learning difficulties/intellectual disability
• Social impairments with or without a diagnosis of autism spectrum disorder (ASD)
• Macrocephaly
• Chiari I/cerebellar tonsillar ectopia
• Seizures/epilepsy
• Vertebral anomalies
• Obesity starting in adolescence, and in the setting of developmental delay

Establishing the Diagnosis

The diagnosis of the 16p11.2 recurrent microdeletion is established by demonstration of deletion of the ~593-kb critical region at the approximate position of 29.6-30.2 Mb in the reference genome (GRCh37/hg19) (see Table 1 and Molecular Genetics).

Of note, an adjacent (distal) recurrent 16p11.2 microdeletion (GRCh37/hg19 chr16:28.8-29.0 Mb) which is also associated with variable features is not discussed further as this GeneReview addresses the 29.6-30.2-Mb recurrent deletion only.

Molecular methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted deletion analysis by fluorescence in situ hybridization (FISH). Note: The 16p11.2 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

• Chromosomal microarray (CMA) using oligonucleotide arrays or SNP genotyping arrays can detect the recurrent deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 16p11.2 region.
  Note: (1) Most individuals with 16p11.2 recurrent microdeletion are identified by CMA performed in the context of evaluation of developmental delay, intellectual disability, or ASD. (2) Prior to 2008 many CMA platforms did not include coverage for this region and thus may not have detected this deletion.
• Targeted deletion analysis. FISH analysis, quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods may be used to test relatives of a proband known to have the 16p11.2 recurrent microdeletion.
  Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 16p11.2 recurrent microdeletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.

Evaluating at-risk relatives. FISH, qPCR, or other quantitative methods of targeted deletion analysis can be used to identify the 16q11.2 recurrent microdeletion in at-risk relatives of the proband. Testing parental samples is important in determining recurrence risk (see Genetic Counseling).

Clinical Description

The 16p11.2 recurrent microdeletion was first reported in individuals with autism spectrum disorder (ASD) [Kumar et al 2008, Marshall et al 2008, Weiss et al 2008]. Prior to that, this 16p11.2 recurrent 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].

Clinical follow-up data from adults suggests that the greatest medical challenges are obesity and related comorbidities that can be exacerbated by medications used to treat behavioral and psychiatric problems.

Males and females are equally affected.

Cognitive impairment. On average, the IQ of individuals with the 16p11.2 recurrent microdeletion is approximately 2 SD lower than other family members without the deletion. Average IQ was 82.7, representing a 26.8-point (1.8 SD) shift downward compared to the full scale IQ average of 109.5 of familial controls [Hanson et al 2015].

Other developmental delay. Most, if not all, individuals with the 16p11.2 recurrent microdeletion experience some degree of developmental delay, although the severity varies. Developmental coordination (motor) disorder was one of the most common diagnoses in individuals with the 16p11.2 recurrent microdeletion, followed by phonologic processing disorder, language disorders, and ASD [Hanson et al 2015].

In the authors' clinical experience, most individuals with the 16p11.2 recurrent microdeletion have been ascertained through genetic testing performed in the evaluation of developmental delay, intellectual disability, or ASD. Although developmental delays in this population are more related to diminished language and cognitive function, they can also involve problems with gross and fine motor skills.

Language delay. About 70% of individuals with 16p11.2 recurrent microdeletion have one or more speech/language-related diagnoses. Overall, expressive language appears to be more affected than receptive language and phonologic (articulation) issues are the most common diagnosis given [Hanson et al 2015].

Children do acquire verbal skills but have significant issues with verbal communication including apraxia for the first five years of life.

It is speculated that these delays in speech and language development may contribute to behavior problems.

Autistic features. Individuals with the 16p11.2 recurrent microdeletion identified in the earliest reported research studies were ascertained primarily through cohorts of individuals with an ASD. Although not all individuals with the 16p11.2 recurrent microdeletion meet diagnostic criteria for ASD, almost all have some behavioral traits shared with ASD including insistence on sameness, reduced scope of interest, repetitive behaviors, and problems with social communication [Zufferey et al 2012, Hanson et al 2015, Moreno-De-Luca et al 2015].

Based on current literature reports, ASD is diagnosed in approximately 20% of individuals with the 16p11.2 microdeletion (i.e, with much greater frequency than in the general population, in which ASD is diagnosed in ~1:68 children).

In a study by Hanson et al [2010], 11 individuals with the 16p11.2 recurrent microdeletion were evaluated for ASD using detailed measures including the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview: three of the 11 met full criteria for ASD (i.e., cutoffs on both measures); six had findings of ASD but did not meet full criteria; and two 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].

More recently Hanson et al [2015] assessed 85 individuals with the 16p11.2 recurrent microdeletion with the detailed measures reported above and found that 24% had ASD. The majority of individuals with the deletion who did not meet full criteria for ASD had significantly higher rates of autism-related characteristics (e.g., social and behavioral difficulties and repetitive and stereotyped behaviors) when compared to family members who did not have the deletion.

Psychiatric disease and behavioral issues. Hanson et al [2015] reported that 93% of individuals with the 16p11.2 microdeletion had at least one psychiatric diagnosis, compared to 21% of familial controls. The mean number of diagnoses in family members who did not have the deletion was 0.3; individuals with the deletion had an average of 2.9 diagnoses. These differences persisted after controlling for having ASD.

Individuals with 16p11.2 microdeletion were found to have significantly higher levels and numbers of behavioral issues than familial controls [Hanson et al 2015].

Hanson et al [2010] did not find a link to ADHD although affective problems, somatic issues, and anxiety were commonly reported.

Neurologic issues

• Seizures are seen in about 20% of individuals with the 16p11.2 recurrent microdeletion. In a case report, one affected individual had EEG abnormalities without overt seizures [Rosenfeld et al 2010]. Heterozygous loss-of-function PRRT2 pathogenic variants (which cause paroxysmal kinesigenic dyskinesia; see following) also cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome [Heron et al 2012], both of which have been reported in a number of individuals with the 16p11.2 recurrent microdeletion.
• Paroxysmal kinesigenic dyskinesia has been observed in a number of individuals with the 16p11.2 recurrent deletion [Termsarasab et al 2014]. Onset of movement-induced choreoathetosis and/or dystonia begins between ages six and 15 years with increasing frequency of paroxysms with age. Of note, loss-of-function heterozygous pathogenic variants in PRRT2, located at 16p11.2, have been identified as a cause of autosomal dominant paroxysmal kinesigenic dyskinesia [Chen et al 2011, Wang et al 2011, Lee et al 2012, Li et al 2012].
• Handedness. Of 75 of individuals with the 16p11.2 microdeletion, 19% had left hand dominance and 29% had mixed dominance compared to 3% and 11%, respectively, of family members without the deletion [Hanson et al 2015].
• Neuroimaging findings are mostly nonrecurrent abnormalities such as arachnoid cyst [Bijlsma et al 2009], prominent extra-axial CSF spaces and ventricles [Shinawi et al 2010], mega cisterna magna, and cavernous malformation [Rosenfeld et al 2010].
  The most common recurrent structural brain abnormalities are posterior fossa and/or craniocervical junction-related abnormalities (e.g., Chiari I malformation, cerebellar tonsillar ectopia, platybasia) [Zufferey et al 2012]. In one case report, two persons with 16p11.2 microdeletion were reported to have syringomyelia (accompanied by a Chiari I malformation in one) [Schaaf et al 2011].
  Quantitative structural MRI analysis has shown a pervasive increase in volume throughout the brain, with white matter and thalami being the most dramatically affected [Qureshi et al 2014].

Obesity. The 16p11.2 recurrent microdeletion is 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).

Overall, several studies show that obesity is a feature of 16p11.2 microdeletion and that the prevalence of overweight and obesity in individuals with 16p11.2 microdeletion is higher than in the general population [Ghebranious et al 2007, Bijlsma et al 2009, Bochukova et al 2010, Fernandez et al 2010, Shinawi et al 2010, Walters et al 2010, Jacquemont et al 2011, Gill et al 2014]. Longitudinal studies show that the weight increase starts about age nine years and becomes increasingly problematic into adulthood, especially with use of certain medications used to treat problematic behaviors.

Cardiac malformations and disease associations. Most individuals in whom the diagnosis of 16p11.2 microdeletion is confirmed have not had diagnostic cardiac imaging; however, limited clinical reports suggest that the incidence of cardiac malformations is slightly increased. Congenital heart disease was identified in 6% of 233 individuals with the 16p11.2 recurrent microdeletion [Zufferey et al 2012].

Other medical issues. Although consistent patterns of other medical problems are not observed, the following have been reported in individuals with the 16p11.2 recurrent microdeletion:

• Height is slightly below average for individuals who are not overweight and may be average for individuals who are overweight.
• Vertebral anomalies (often associated with scoliosis) were observed in 21% of 233 individuals with the microdeletion [Zufferey et al 2012].
• Macrocephaly is frequently observed, usually becomes apparent by age two years, and is usually not secondary to hydrocephalus.
• Craniosynostosis was observed in 2% of 233 individuals [Zufferey et al 2012].
• Hearing impairment (sensorineural and conductive hearing loss) is seen in up to 11% of individuals.
• A characteristic pattern of dysmorphic features that would facilitate a clinical diagnosis is not observed in individuals with the16p11.2 recurrent microdeletion. However, several studies have reported on various dysmorphic features [Bijlsma et al 2009, Rosenfeld et al 2010, Shinawi et al 2010].
• Severe combined immunodeficiency (SCID) was reported in one individual with 16p11.2 microdeletion on one chromosome 16 and a single-nucleotide variant in CORO1A on the other chromosome 16 [Shiow et al 2009].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed.

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]. That number is supported by more recent data showing 16p11.2 deletion in approximately 3.5 of 10,000 individuals from a larger, but overlapping, cohort of more than 76,000 Icelandic individuals [Stefansson et al 2014]. 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.

16p11.2 recurrent 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 the recurrent microdeletion of 16p11.2 [Bijlsma et al 2009]. Individuals identified in these reports did not have a recognizable clinical phenotype.

Data drawing on the large ClinGen database of more than 15,000 cases tested in clinical labs demonstrates that the 16p11.2 deletion is the second most commonly identified microdeletion, occurring in one of every 235 cases tested [Kaminsky et al 2011].

Evaluations Following Initial Diagnosis

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

• Routine clinical examination, including dysmorphology examination and broad review of all organ systems
• Measurement of height and weight
• Evaluate for hypertension and diabetes in patients who are overweight or obese
• Developmental assessment with cognitive and behavioral testing, including neuropsychological testing by a clinical psychologist
• Consultation with a neurologist (with possible EEG and MRI) if history suggests possible seizures
• Consideration of brain MRI for headache (especially occipital), neck pain, oropharyngeal dysfunction, or other manifestations of brain stem dysfunction
• Diagnostic radiograph of the spine to evaluate for vertebral anomalies/scoliosis
• Consideration of evaluation and echocardiogram by a cardiologist if a heart murmur is detected
• Audiologic testing
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Manifestations of the 16p11.2 recurrent microdeletion are variable, and treatment should be targeted to the specific findings identified.

Early diagnosis and provision of therapies facilitate the best outcome. Referral to other appropriate medical specialists (e.g., a developmental/behavioral pediatrician, pediatric neurologist, and/or clinical geneticist) is recommended based on specific symptoms or signs.

Neurodevelopmental disabilities including autism spectrum disorder (ASD). 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.

Guidelines for management of individuals with ASD are available from the American Academy of Pediatrics [Myers et al 2007] (full text).

Seizures. Choice of antiepileptic medication is guided by patient age, seizure type, EEG and imaging findings, side effect profiles, and response to treatment. No specific antiepileptic medications have been identified to be most effective.

Paroxysmal kinesigenic dyskinesia is responsive to low doses of carbamazepine and phenytoin.

Obesity and overweight. It is important to initiate weight management and nutrition counseling in young children before excessive weight gain begins. Control food intake with normal portion sizes and limitation of food intake between meals. Maintain an active lifestyle. Increased calories are specifically ingested in the absence of hunger and suggest that close supervision of portion size and meal times can be beneficial.

Chiari I malformation or syringomyelia. Brain and spine MRI are indicated for new or progressive symptoms suggestive of a Chiari I malformation or syringomyelia, including sleep apnea, dysarthria, dysphagia, gait disturbance, and scoliosis.

Surveillance

Routine developmental surveillance and screening are recommended because of the increased incidence of developmental delay, intellectual disability, and autism. See the American Academy of Pediatrics guidelines on surveillance and screening to identify patients with developmental disorders in general [Council on Children with Disabilities 2006] and autism in particular [Johnson et al 2007] and recommendations for management of children with ASD [Myers et al 2007] (Published Guidelines / Consensus Statements).

Surveillance should include the following:

• Monitoring of height, weight, and BMI
• Monitoring for abnormal movements, staring spells, or other events of concern for possible seizures
• Monitoring for headache (especially occipital), neck pain, and other symptoms of brain stem or spinal cord dysfunction that could indicate Chiari malformations/cerebellar ectopia, and neurologic consultation and brain MRI if indicated
• Clinical screening for scoliosis until the age of skeletal maturity
• Annual evaluation and monitoring of hearing in first three years of life
• Periodic reevaluation by a clinical geneticist to apprise the family of new developments and/or recommendations and facilitate long-term monitoring for emerging medical or mental health concerns

Agents/Circumstances to Avoid

Some medications used to treat behavioral problems (e.g., clozapine, olanzapine) may lead to excessive weight gain. When possible, use medications that are not associated with weight gain.

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 in the US and EU Clinical Trials Register in Europe 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.