Autism

AUTISM/16p11.
2 DELETION SYNDROME (Susceptibility to

Autism Spectrum Disorders, MIM 611913)
Autosomal Dominant or De Novo
PRINCIPLES a newly described condition, the prevalence of 16p11.2 micro-

deletion syndrome is still being determined. About 1% of
• New technology adding to diagnostic yield individuals tested by array comparative genome hybridization
• Copy number variant (benign and pathogenic) (CGH) for autism spectrum disorder (ASD) have the common
• Variant of uncertain significance 16p11.2 microdeletion, and 0.1% of people tested for devel-
• Gene dosage effect opmental delay or a psychiatric condition carry it while only
• Susceptibility loci 0.03% of people in the general population carry the microde-
• Incomplete penetrance letion. Most microdeletions at 16p11.2 are de novo, but some
are inherited from symptomatic parents or from healthy, cog-
MAJOR PHENOTYPIC FEATURES nitively normal parents. Therefore incomplete penetrance is
evident in this condition.
• Age at onset: Birth or first 6 months of life
• Intellectual disability to normal intelligence Pathogenesis
• Impaired social and communication skills or frank autism 16p11.2 microdeletion is one of many microdeletion/
spectrum disorder microduplications that recur due to low-copy repeat sequences
• Minor dysmorphic features (LCRs) with high sequence homology flanking the deleted or
duplicated DNA (see Chapter 6). During replication, the DNA
HISTORY AND PHYSICAL FINDINGS misaligns on these LCRs, causing nonallelic homologous
recombination (NAHR) and consequent deletion or duplica-
M.L., a 3-year-old boy, was referred to a medical genetics clinic tion of the DNA between the LCRs. It is unclear which of the
to identify the cause of his speech delay. Pregnancy and birth 25 known genes in the interval leads to ASD and other phe-
were uneventful. He walked around 14 months of age, and notypic manifestations of the condition. Sequencing of many
spoke his first words at 30 months. At 3 years of age, he had of these genes in individuals with autism has revealed muta-
five words. His parents felt that he understood more than he tions in several genes, but further studies are needed to vali-
could communicate, although his receptive language was also date these results.
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 Phenotype and Natural History
transverse palmar crease on the left hand, and bilateral 2/3/4
toe syndactyly. His parents described him as a “loner”; he 16p11.2 microdeletion syndrome is characterized by suscepti-
preferred to play alone rather than with his siblings or peers. bility to developmental delay/intellectual disability and/or
Concerning behaviors included becoming very agitated with ASD. Typically the delays present in children with 16p11.2
loud noises or irritating textures such as his shirt tag and microdeletion are more pronounced in speech/language skills
throwing tantrums when his routine was changed. He was and socialization rather than motor functioning. Expressive
interested only in cars but preferred to play with their wheels language is usually more affected than receptive language.
or place them in groups rather than racing them. In the Features of ASD occur more frequently in this population than
meantime, the geneticist ordered a chromosome microarray the general population, but the percentage of affected indi-
and fragile X DNA studies, due to his developmental delay viduals who have a diagnosis of ASD is controversial and is
with autistic features and mild dysmorphic features. The fragile certainly not 100%. Individuals with 16p11.2 microdeletion
X DNA test was normal. However, the single nucleotide are more likely to be overweight or obese, particularly in
polymorphism array revealed two copy number variants: a adolescence and adulthood, perhaps due to haploinsufficiency
550-kb deletion at 16p11.2 (thought to be pathogenic) and a of SH2B1 and/or other genes. Seizures are somewhat more
526-kb duplication at 21q22.12 (a variant of uncertain common in this population than the general population.
significance). Parental studies showed M.L.’s mother had the Some individuals with this deletion have been found to
21q duplication, but the 16p11.2 deletion was de novo. The have aortic valve abnormalities; a majority of individuals do
family was counseled that the 16p11.2 deletion was likely the not have heart malformations. Minor dysmorphic features
cause of M.L.’s autistic features and delays, and the 21q22.12 may be present, but no specific features are characteristic of
duplication was likely a benign variant. 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 intel-
lectual disability and ASD features are not universal in this
BACKGROUND condition.
The reciprocal 16p11.2 microduplication carries a 14.5-
Disease Etiology and Incidence fold increased risk for schizophrenia over the general popula-
16p11.2 microdeletion syndrome (MIM 611913) is an auto- tion. This duplication has also been found in individuals with
somal dominant condition caused by an approximately 550-kb developmental delay/intellectual disability, ASD, and bipolar
contiguous gene deletion on chromosome 16p11.2 (Fig. C-5). disorder. However, the 16p11.2 microduplication has been
This recurring microdeletion contains 25 annotated genes. As found in healthy controls and is more likely to be inherited
CASE 5 — AUTISM/16P11.2 DELETION SYNDROME 401
16p11.2
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.
from a healthy parent than the microdeletion. Thus the dupli- INHERITANCE RISK
cation probably increases susceptibility to delays or psychiat-
16p11.2 deletion is usually de novo but can be inherited from
ric disorders with low penetrance.
a parent. When de novo, the recurrence risk for the parents is
Array CGH is a powerful tool that has identified the etiol-
less than 5%, taking into account the risk for gonadal mosa-
ogy of developmental delay/intellectual disability, develop-
icism. If one parent also carries the deletion, recurrence risk
mental disorders such as ASD, and/or multiple congenital
for the deletion is 50% for each subsequent pregnancy. There-
anomalies in up to 20% of individuals tested. In general, the
fore, in order to provide appropriate genetic counseling, it is
technology has changed the way that medical geneticists prac-
crucial to perform parental studies when a 16p11.2 abnormal-
tice (see Chapters 5 and 6). However, uncertainty regarding
ity is diagnosed in a child. However, due to incomplete pen-
results is an ever-present dilemma; variants of uncertain sig-
etrance, a child who inherits the deletion may not be affected
nificance (VUSs; see Chapter 16) abound. Several recommen-
with the same features as his or her sibling and may exhibit
dations have arisen to help determine the pathogenicity of
normal intelligence and behavior. Alternatively, an affected
results. The size and dosage effect of the CNV is important;
child may have more significant intellectual disability, autistic
loss of genomic material and large variations are more detri-
features, and/or health concerns.
mental than gains and small changes, in general. However,
small CNVs in a gene-rich area can cause phenotypic mani-
festations, 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 REFERENCES
inherited VUS from a phenotypically normal parent is histori-
cally considered less likely to be pathogenic. However, as with McCarthy S, Makarov V, Kirov G, et al: Microduplications of 16p11.2 are associated
16p11.2 microdeletion and microduplication syndromes, with schizophrenia, Nat Genet 41:1223–1227, 2009.
incomplete penetrance can exist with many CNVs; therefore Miller DT, Nasir R, Sobeih MM, et al: 16p11.2 Microdeletion. Available from: http://
an inherited VUS cannot be ruled benign based only on this www.ncbi.nlm.nih.gov/books/NBK11167/.
Simons VIP Consortium: Simons Variation in Individuals Project (Simons VIP): a
information. genetics-first approach to studying autism spectrum and related neurodevelop-
Because of the potential for ambiguous results, providing mental disorders, Neuron 73:1063–1067, 2012.
genetic counseling to a family regarding the possible implica- Unique, the Rare Chromosomal Disorder Support Group. Available from: http://
tions of testing both before and after array CGH testing is www.rarechromo.org.
beneficial. Weiss LA, Shen Y, Korn JM, et al: Association between microdeletion and micro-
duplication at 16p11.2 and autism, N Engl J Med 358:667–675, 2008.
Management
Because of the higher prevalence of developmental delay/
intellectual disability and ASD features in individuals with
16p11.2 microdeletion, referral to a developmental pediatri-
cian or clinical psychologist is recommended for developmen-
tal 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.

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AUTISM/16p11.

2 DELETION SYNDROME (Susceptibility to

PRINCIPLES a newly described condition, the prevalence of 16p11.2 micro-

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