Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications

Abstract

Microdeletions and microduplications encompassing a ~593-kb region of 16p11.2 have been implicated as one of the most common genetic causes of susceptibility to autism/autism spectrum disorder (ASD). We report 45 microdeletions and 32 microduplications of 16p11.2, representing 0.78% of 9,773 individuals referred to our laboratory for microarray-based comparative genomic hybridization (aCGH) testing for neurodevelopmental and congenital anomalies. The microdeletion was de novo in 17 individuals and maternally inherited in five individuals for whom parental testing was available. Detailed histories of 18 individuals with 16p11.2 microdeletions were reviewed; all had developmental delays with below-average intelligence, and a majority had speech or language problems or delays and various behavioral problems. Of the 16 individuals old enough to be evaluated for autism, the speech/behavior profiles of seven did not suggest the need for ASD evaluation. Of the remaining nine individuals who had speech/behavior profiles that aroused clinical suspicion of ASD, five had formal evaluations, and three had PDD-NOS. Of the 19 microduplications with parental testing, five were de novo, nine were maternally inherited, and five were paternally inherited. A majority with the microduplication had delayed development and/or specific deficits in speech or language, though these features were not as consistent as seen with the microdeletions. This study, which is the largest cohort of individuals with 16p11.2 alterations reported to date, suggests that 16p11.2 microdeletions and microduplications are associated with a high frequency of cognitive, developmental, and speech delay and behavior abnormalities. Furthermore, although features associated with these alterations can be found in individuals with ASD, additional factors are likely required to lead to the development of ASD.

Fig. 1

High-resolution microarray analysis of 16p11.2 rearrangements. Refinement of 16p11.2 microdeletion breakpoints by high-density microarray analysis, for a representative set of cases, is shown. Note that probes with log₂ ratios above or below a threshold of 1.5 standard deviations from the normalized mean log₂ ratio are colored green (duplication) or red (deletion), respectively. Dotted lines represent breakpoint regions (BP). Segmental duplications flanking the 16p11.2 rearrangements are also shown. The orange and blue boxes represent homologous segmental-duplication blocks, 147 kb and 72 kb respectively, participating in the NAHR event for this particular rearrangement

Fig. 2

Physical features in individuals with 16p11.2 microdeletions. Individuals are aged <1 year a, 2 years b, 3 years c, d, 4 years e, f, 8 years g, 9 years h, 10 years i, j, 18 years k and 20 years l. m Foot of individual shown in (k). Note 2–3 syndactyly and small toenails. n Profile of individual shown in (g). Note hypoplastic ear with Darwinian tubercle and fleshy lobe. Ears are also fleshy and/or prominent in individuals (b, e, i, j). Individual (g) also has bilateral iris coloboma. Other features noted include frontal bossing (f, j, k), flattened midface (h, j, k), broad nose (b, e), retrognathia (a, j, k), short, thick, or webbed neck (e, g, j), downturned mouth (e, g, h) and synophrys (k, j)

Fig. 3

Physical features in individuals with 16p11.2 microduplications. a, b 7-year-old male with epicanthal folds, broad nose, frontal hair whorl, wide mouth and low-set ears. c, d, e Siblings aged 6, 2, and their mother (age 38), all of whom have a 16p11.2 microduplication. Note thin upper lip and prominent forehead