AUTISM/16p11.
2 DELETION SYNDROME (Susceptibility to
Autism Spectrum Disorders, MIM 611913)
Autosomal Dominant or De Novo
PRINCIPLES
• 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.
BACKGROUND
Disease Etiology and Incidence
16p11.2 microdeletion syndrome (MIM 611913) is an auto-
somal 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 micro-
deletion 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 devel-
opmental delay or a psychiatric condition carry it while only
0.03% of people in the general population carry the microde-
letion. Most microdeletions at 16p11.2 are de novo, but some
are inherited from symptomatic parents or from healthy, cog-
nitively normal parents. Therefore incomplete penetrance is
evident in this condition.
Pathogenesis
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 duplica-
tion of the DNA between the LCRs. It is unclear which of the
25 known genes in the interval leads to ASD and other phe-
notypic manifestations of the condition. Sequencing of many
of these genes in individuals with autism has revealed muta-
tions in several genes, but further studies are needed to vali-
date these results.
Phenotype and Natural History
16p11.2 microdeletion syndrome is characterized by suscepti-
bility 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 indi-
viduals 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 intel-
lectual 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 popula-
tion. 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
 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.