Further characterization of the new microdeletion syndrome of 16p11.2–p12.2

Abstract

Using aCGH, we have identified a pericentromeric deletion, spanning about 8.2 Mb, within 16p11.2-p12.2 in a patient with developmental delay (DD) and dysmorphic features. This deletion arose de novo and is flanked by segmental duplications. The proposita was the only child of healthy nonconsanguineous parents, born after an uneventful pregnancy, at 40 weeks gestation, by normal delivery. She was referred to us at age 3 10/12 years for evaluation of DD and absent speech. On examination, there were a flat face; low-set, posteriorly rotated ears; high-arched palate; hypotonic face; right single palmar crease; long, thin fingers; and a sacral dimple. Her height was at the 50th centile, weight at the 25th, and OFC at the 30th. Results of DNA FraX, HRB chromosomes, metabolic work-up, audiologic evaluation, brain MRI, electroencephalogram, and heart/abdomen ultrasonography were normal. When last seen, aged 8 years, she had a moderate intellectual disability (ID) and poor speech. She was hyperactive with short attention span and difficulty in concentration, but, based on formal testing, did not have autism. Our patient shows common clinical features to the four individuals described by Ballif et al. [Ballif et al. (2007); Nat Genet 39:1071-1073], and further characterizes the new microdeletion syndrome of 16p11.2-p12.2. aCGH suggests that the deletions of all cases share the same distal breakpoint. Of note, the proximal breakpoint of our proposita overlaps the distal breakpoint of the autistic patients studied by Kumar et al. [Kumar et al. (2008); Hum Mol Genet 17:628-638] and Weiss et al. [Weiss et al. (2008); N Eng J Med 358:667-675], confirming that the 16p region carrying susceptibility to autism is more centromeric. Our observation further defines two different, contiguous 16p genomic regions, responsible for a distinct MCA/ID syndrome, and for autism, respectively.

Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother

“…12 The six deletion carriers described so far exhibit similar dysmorphic features, ID, severe language impairment, short stature, feeding difficulties and recurrent ear infections. [12][13][14] None was reported to have autism or autistic traits, although only one was assessed formally for ASD. 13 These subjects share a common distal breakpoint around 21.4 Mb, but differ in the proximal breakpoint, ranging from 28.5 to 30.1 Mb.…”

“…[12][13][14] None was reported to have autism or autistic traits, although only one was assessed formally for ASD. 13 These subjects share a common distal breakpoint around 21.4 Mb, but differ in the proximal breakpoint, ranging from 28.5 to 30.1 Mb. 12 Our patients are the first with a molecularly characterized 16p11.2p12.2 duplication.…”

“…10,11 Another microdeletion syndrome in 16p11.2p12.2 involving a B7-9 Mb region (with a common distal breakpoint at 21.4 Mb and proximal breakpoints varying between 28.5 and 30.1 Mb) was identified recently in six patients with common dysmorphic features and developmental delay without autism. [12][13][14] Three patients carrying a 16p11.2p12.2 duplication had been described earlier, 15,16 but as these cases were studied by standard cytogenetic and fluorescence in situ hybridization (FISH) techniques, it is difficult to prove that they are the reciprocal duplication product of the 16p11.2p12.2 microdeletion syndrome. The three patients had ASD and short stature, but only one had ID and dysmorphic features.…”

Genomics, Intellectual Disability, and Autism

“…Deletions of 16p11.2 were first identified in patients with autism 29,79 and are present in up to 1% of those with autism spectrum disorders, but it is now clear that such deletions are also associated with intellectual disability without autistic features. [59][60][61][62]80 Deletions of the same region are also associated with early-onset obesity in subjects with and those without developmental delays. 63,64 The 16p11.2 deletion is associated with dysmorphic features, but like the 1q21.1 rearrangement, it is not associated with a recognizable constellation of clinical features.…”

“…Brunetti-Pierri et al, 32 Mefford et al, 33 International Schizophrenia Consortium, 34 Stefansson et al, 35 Greenway et al, 36 Haldeman-Englert and Jewett 37 3q29 Stefansson et al, 35 de Kovel et al, 43 Mefford et al, 44 Burnside et al, 45 Doornbos et al, 46 Murthy et al, 47 35 Helbig et al, 49 Sharp et al, 50 van Bon et al, 51 Ben-Shachar et al, 52 Pagnamenta et al, 53 29 Battaglia et al, 59 Bijlsma et al, 60 Hempel et al, 61 Shinawi et al, 62 Jacquemont et al, 63 43 Mefford et al, 44 Heinzen et al, 69 Williams et al, 70 Ullmann et al, 71 …”