Autosomal Dominant or De Novo
• New technology adding to diagnostic yield
• Copy number variant (benign and pathogenic)
• Variant of uncertain significance
• Gene dosage effect
• Susceptibility loci
• Incomplete penetrance
Major Phenotypic Features
• Age at onset: Birth or first 6 months of life
• Intellectual disability to normal intelligence
• Impaired social and communication skills or frank autism spectrum disorder
• Minor dysmorphic features
History and Physical Findings
M.L., a 3-year-old boy, was referred to a medical genetics clinic to identify the cause of his speech delay. Pregnancy and birth were uneventful. He walked around 14 months of age, and spoke his first words at 30 months. At 3 years of age, he had five words. His parents felt that he understood more than he could communicate, although his receptive language was also delayed. M.L. had no medical concerns, and his family history was noncontributory. A physical examination revealed minor dysmorphic features, including simple, low-set ears, a single transverse palmar crease on the left hand, and bilateral 2/3/4 toe syndactyly. His parents described him as a “loner”; he preferred to play alone rather than with his siblings or peers. Concerning behaviors included becoming very agitated with loud noises or irritating textures such as his shirt tag and throwing tantrums when his routine was changed. He was interested only in cars but preferred to play with their wheels or place them in groups rather than racing them. In the meantime, the geneticist ordered a chromosome microarray and fragile X DNA studies, due to his developmental delay with autistic features and mild dysmorphic features. The fragile X DNA test was normal. However, the single nucleotide polymorphism array revealed two copy number variants: a 550-kb deletion at 16p11.2 (thought to be pathogenic) and a 526-kb duplication at 21q22.12 (a variant of uncertain significance). Parental studies showed M.L.'s mother had the 21q duplication, but the 16p11.2 deletion was de novo. The family was counseled that the 16p11.2 deletion was likely the cause of M.L.'s autistic features and delays, and the 21q22.12 duplication was likely a benign variant.
Disease Etiology and Incidence
16p11.2 microdeletion syndrome (MIM 611913) is an autosomal dominant condition caused by an approximately 550-kb contiguous gene deletion on chromosome 16p11.2 (Fig. C-5). This recurring microdeletion contains 25 annotated genes. As a newly described condition, the prevalence of 16p11.2 microdeletion syndrome is still being determined. About 1% of individuals tested by array comparative genome hybridization (CGH) for autism spectrum disorder (ASD) have the common 16p11.2 microdeletion, and 0.1% of people tested for developmental delay or a psychiatric condition carry it while only 0.03% of people in the general population carry the microdeletion. Most microdeletions at 16p11.2 are de novo, but some are inherited from symptomatic parents or from healthy, cognitively normal parents. Therefore incomplete penetrance is evident in this condition.
FIGURE C-5 Chromosomal microarray analysis of a 16p11.2 deletion in a patient with autism spectrum disorder. Chromosome 16 ideogram with probe coverage (dots) along the length of the chromosome. The log2 ratio scale is shown on the left; probes with a normal ratio are shown in black, whereas probes with a ratio suggestive of either a loss or gain are shown in green and red, respectively. The deleted region is highlighted (pink) in the expanded region of the figure below. The red bar corresponds to the deleted region (≈600 kb), which is flanked by paired segmental duplications that mediate the deletion. See Sources & Acknowledgments.
16p11.2 microdeletion is one of many microdeletion/microduplications that recur due to low-copy repeat sequences (LCRs) with high sequence homology flanking the deleted or duplicated DNA (see Chapter 6). During replication, the DNA misaligns on these LCRs, causing nonallelic homologous recombination (NAHR) and consequent deletion or duplication of the DNA between the LCRs. It is unclear which of the 25 known genes in the interval leads to ASD and other phenotypic manifestations of the condition. Sequencing of many of these genes in individuals with autism has revealed mutations in several genes, but further studies are needed to validate these results.
Phenotype and Natural History
16p11.2 microdeletion syndrome is characterized by susceptibility to developmental delay/intellectual disability and/or ASD. Typically the delays present in children with 16p11.2 microdeletion are more pronounced in speech/language skills and socialization rather than motor functioning. Expressive language is usually more affected than receptive language. Features of ASD occur more frequently in this population than the general population, but the percentage of affected individuals who have a diagnosis of ASD is controversial and is certainly not 100%. Individuals with 16p11.2 microdeletion are more likely to be overweight or obese, particularly in adolescence and adulthood, perhaps due to haploinsufficiency of SH2B1 and/or other genes. Seizures are somewhat more common in this population than the general population. Some individuals with this deletion have been found to have aortic valve abnormalities; a majority of individuals do not have heart malformations. Minor dysmorphic features may be present, but no specific features are characteristic of this disorder. Cognitively normal parents of children with 16p11.2 microdeletion syndrome have, however, been found to have the same microdeletion present in the child; thus intellectual disability and ASD features are not universal in this condition.
The reciprocal 16p11.2 microduplication carries a 14.5-fold increased risk for schizophrenia over the general population. This duplication has also been found in individuals with developmental delay/intellectual disability, ASD, and bipolar disorder. However, the 16p11.2 microduplication has been found in healthy controls and is more likely to be inherited from a healthy parent than the microdeletion. Thus the duplication probably increases susceptibility to delays or psychiatric disorders with low penetrance.
Array CGH is a powerful tool that has identified the etiology of developmental delay/intellectual disability, developmental disorders such as ASD, and/or multiple congenital anomalies in up to 20% of individuals tested. In general, the technology has changed the way that medical geneticists practice (see Chapters 5 and 6). However, uncertainty regarding results is an ever-present dilemma; variants of uncertain significance (VUSs; see Chapter 16) abound. Several recommendations have arisen to help determine the pathogenicity of results. The size and dosage effect of the CNV is important; loss of genomic material and large variations are more detrimental than gains and small changes, in general. However, small CNVs in a gene-rich area can cause phenotypic manifestations, whereas large CNVs in a gene-poor region may not. Parents of a child with a VUS should have array or FISH testing to determine if a CNV is inherited or de novo; an inherited VUS from a phenotypically normal parent is historically considered less likely to be pathogenic. However, as with 16p11.2 microdeletion and microduplication syndromes, incomplete penetrance can exist with many CNVs; therefore an inherited VUS cannot be ruled benign based only on this information.
Because of the potential for ambiguous results, providing genetic counseling to a family regarding the possible implications of testing both before and after array CGH testing is beneficial.
Because of the higher prevalence of developmental delay/intellectual disability and ASD features in individuals with 16p11.2 microdeletion, referral to a developmental pediatrician or clinical psychologist is recommended for developmental assessment and placement in appropriate early intervention services, such as physical, occupational, and speech therapies. Social, behavioral, and educational interventions are also available for children with ASDs. An echocardiogram and/or electrocardiogram should be considered to look for aortic valve or other structural heart anomalies, and referral to a pediatric neurologist should be made if there is suspicion of seizure activity. Weight management and nutritional support should be provided because of the increased risk for obesity.
16p11.2 deletion is usually de novo but can be inherited from a parent. When de novo, the recurrence risk for the parents is less than 5%, taking into account the risk for gonadal mosaicism. If one parent also carries the deletion, recurrence risk for the deletion is 50% for each subsequent pregnancy. Therefore, in order to provide appropriate genetic counseling, it is crucial to perform parental studies when a 16p11.2 abnormality is diagnosed in a child. However, due to incomplete penetrance, a child who inherits the deletion may not be affected with the same features as his or her sibling and may exhibit normal intelligence and behavior. Alternatively, an affected child may have more significant intellectual disability, autistic features, and/or health concerns.
Questions for Small Group Discussion
1. Name other recurring microdeletion/microduplication syndromes caused by LCRs. What might be the impact of array CGH in detecting new recurrent syndromes?
2. In performing array CGH testing and whole-exome sequencing, what are some results that may give arise to ethical dilemmas? How would you counsel patients with these types of results, before and after the testing is ordered?
3. Deletions of a particular genomic region are typically more severe than duplications of the same region. In what situations would a duplication create a greater health risk than a deletion?
4. Why was a karyotype not ordered for this patient? Is there ever an indication for a karyotype? If so, what is it/are they?
McCarthy S, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009;41:1223–1227.
Miller DT, Nasir R, Sobeih MM, et al. 16p11.2 Microdeletion. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK11167/.
Simons VIP Consortium. Simons Variation in Individuals Project (Simons VIP): a genetics-first approach to studying autism spectrum and related neurodevelopmental disorders. Neuron. 2012;73:1063–1067.
Unique, the Rare Chromosomal Disorder Support Group. [Available from] http://www.rarechromo.org.
Weiss LA, Shen Y, Korn JM, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008;358:667–675.