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The prevalence of proximal 16p11.2 microdeletion syndrome is estimated at 1/5,000 in the general population. Proximal 16p11.2 microdeletion syndrome is a common etiology in autism spectrum disorder (ASD) estimated at approximately 1:150 individuals diagnosed with ASD.

The clinical presentation of proximal 16p11.2 microdeletion syndrome can be extremely variable, ranging from intellectual deficiency with multiple congenital anomalies, autism, cognitive and language problems, to a normal phenotype. Nearly all individuals do present with some degree of developmental delay including a cognitive delay and a language delay specifically in the onset and development of expressive language (childhood apraxia of speech) as well as to a lesser extent feeding difficulties, linked to hypotonia and a delay in gross and fine motor and coordination skills. Furthermore, they often present with autistic features. Intellectual disability is usually mild but can be absent. About half of affected individuals have a tendency to be overweight. Dysmorphic features may be present but are often mild and inconsistent. Additional less frequent features reported include hypotonia, EEG abnormalities, psychiatric disease other than ASD and minor cardiac anomalies.

The proximal 16p11.2 microdeletion syndrome most commonly refers to a distinct deletion of approximately 593 kb at chromosomal coordinates 29.5-30.1 Mb comprising 24 genes. The relationship between genotype and clinical phenotype remains elusive. Patients with larger deletions including this region or patients with a more distally located (coordinates 28.73-28.95 Mb), smaller (200 kb) 16p11.2 deletion are not described here.

Diagnosis is based on clinical manifestations leading to chromosomal analysis. Molecular techniques that may be used for the genetic characterization of the proximal 16p11.2 microdeletion include fluorescence in situ hybridization (FISH), Multiplex Ligation-dependent Probe Amplification (MLPA), Microarray-based Comparative Genomic Hybridization (aCGH) and quantitative polymerase chain reaction (qPCR). Electroencephalographic (EEG) testing is performed in cases with seizures.

Differential diagnosis includes many entities presenting with a developmental delay with or without autistic features and minor dysmorphisms.

In cases with a family history, preimplantation genetic diagnosis or prenatal testing is technically feasible by amniocentesis or chorionic villus sampling and cytogenetic analyses, but genetic counseling for affected individuals should be provided before starting a family. The outcome of the genetic diagnosis cannot accurately predict the clinical phenotype.

Proximal 16p11.2 microdeletion syndrome is a contiguous deletion syndrome. Proximal 16p11.2 microdeletions almost always appear de novo, but may, in a small number of cases, be inherited from affected parents in an autosomal dominant manner.

Management involves a regular assessment by appropriate specialists and tailored neurodevelopmental therapies. Early diagnosis and access to therapies with attention to speech and language are recommended together with nutritional education and weight management.

Prognosis depends on the severity of clinical manifestations. Long-term clinical follow-up studies are not available to date. One may expect that the long-term health consequences of obesity occurring in the general population will also occur in individuals with proximal 16p11.2 microdeletion syndrome.