Chromosome 16p11.2 Deletion Syndrome, 220-Kb

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome (chr16:28.73-28.95 Mb).

Description

The deletion of a 220-kb region on chromosome 16p11.2 encompassing approximately 9 genes, including the SH2B1 gene (608937), is associated with a highly penetrant form of isolated severe early-onset obesity as well as obesity with developmental delay (summary by Bachmann-Gagescu et al., 2010).

An extended 1.7-Mb deletion of chromosome 16p11.2 containing both the 220-kb region and the proximal 593-kb region associated autism (see 611913) has been reported in 2 patients with a syndrome of autism, mental retardation, and obesity and in 2 patients with pervasive developmental disorder, auditory processing difficulties, and attention deficit-hyperactivity disorder but not obesity.

For a phenotypic description and a discussion of genetic heterogeneity of body mass index (BMI), see 606641.

Clinical Features

The original descriptions of a 220-kb deletion at chromosome 16p11.2 included patients with severe early-onset obesity (Thorleifsson et al., 2009) and developmental delay (Bochukova et al., 2010).

Clinical Variability

Sampson et al. (2010) reported 3 unrelated boys with a heterozygous 220-kb deletion or extended 1.7-Mb deletion of chromosome 16p11.2 associated with Hirschsprung disease (HSCR; 142623) in 2 and renal anomalies in 2. A 24-day-old boy had left renal agenesis with vesicoureteral reflux (VUR), dilation and tortuosity of the ureter, and normal external genitalia. He had a patent anus, but an aganglionic bowel segment extending to the mid-transverse colon. The second patient was a 17-year-old boy with left renal agenesis, chronic kidney disease, proteinuria, hyperuricemia, and chronic constipation. A rectal biopsy was not performed. Additional features included a seizure disorder, migraine headaches, pervasive developmental disorder, retinal dystrophy, retinitis pigmentosa, and kyphosis. He also had a long oval face with a low anterior hairline, high nasal bridge, and small mouth. The third patient was a 12-year-old boy with genetically confirmed congenital contractural arachnodactyly (CCA; 121050) as well as short-segment HSCR. He had a history of auditory processing difficulties and attention deficit-hyperactivity disorder. Neither of the older boys was obese. Microarray analysis found that the 2 older boys had a common 1.7-Mb deletion (chr16:28.39-30.08), and the newborn boy had a 217-kb deletion that overlapped the larger deletion. The common region of overlap was thus 217 kb in length, which included the SH2B1 gene (608937).

Mapping

To search for sequence variants that affect variation in 2 common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, Thorleifsson et al. (2009) performed a genomewide association study with 305,846 single-nucleotide polymorphisms (SNPs) typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European American, and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. The strongest signals were followed up in additional populations. At the 16p11 locus, the G allele (ala484) of the nonsynonymous SNP rs7498665 (T484A) in the SH2B1 gene (608937) had the strongest association with variations in BMI (combined p = 3.2 x 10(-10)) and weight (combined p = 5.8 x 10(-10)) of 3 associated SNPs within the region.

Willer et al. (2009) performed a metaanalysis of 15 genomewide association studies for BMI comprising 32,387 participants and followed up top signals in 14 additional cohorts comprising 59,082 participants. They identified association of a SNP in the SH2B1 gene, rs7498665, with BMI (p = 2.2 x 10(-14)).

Cytogenetics

Bochukova et al. (2010) investigated the contribution of copy number variation (CNV) to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (greater than 500 kb), rare (less than 1%) deletions were significantly enriched in patients compared with 7,366 controls (P less than 0.001). Bochukova et al. (2010) identified 5 patients with overlapping deletions on chromosomes 16p11.2 that were found in only 2 of 7,366 controls (P less than 5 x 10(-5)). In 3 of these patients, a 220-kb deletion (28.73-28.95 Mb) was inherited from an obese parent and segregated with severe early-onset obesity unassociated with any developmental problem. The other 2 patients harbored a de novo 1.7-Mb deletion of chromosome 16p11.2 extending through the proximal 593-kb region on chromosome 16p11.2 associated with autism and mental retardation (see 611913); both of these patients had mild developmental delay in addition to severe early-onset obesity. In an independent sample of 1,062 patients with severe obesity alone, the same 220-kb deletion was found in an additional 2 patients. All chromosome 16p11.2 deletions encompassed multiple genes but always included SH2B1, which is involved in leptin (164160) and insulin (176730) signaling. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. Bochukova et al. (2010) concluded that CNV contributes significantly to the genetic architecture of human obesity.