Detailed phenotype–genotype study in five patients with chromosome 6q16 deletion: narrowing the critical region for Prader–Willi-like phenotype

Abstract

Most patients with an interstitial deletion of 6q16 have Prader-Willi-like phenotype, featuring obesity, hypotonia, short hands and feet, and developmental delay. In all reported studies, the chromosome rearrangement was detected by karyotype analysis, which provides an overview of the entire genome but has limited resolution. Here we describe a detailed clinical presentation of five patients, two of whom were previously reported, with overlapping interstitial 6q16 deletions and Prader-Willi-like phenotype. Our patients share the following main features with previously reported cases: global developmental delay, hypotonia, obesity, hyperphagia, and eye/vision anomalies. All rearrangement breakpoints have been accurately defined through array-CGH at about 100 Kb resolution. We were able to narrow the shortest region of deletion overlap for the presumed gene(s) involved in the Prader -Willi-like syndrome to 4.1 Mb located at 6q16.1q16.2. Our results support the evidence that haploinsufficiency of the SIM1 gene is responsible for obesity in these patients. A possible involvement of the GRIK2 gene in autistic-like behaviour, of POPDC3 in heart development, and of MCHR2 in the control of feeding behaviour and energy metabolism is also hypothesized.

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

“…Our observations narrow the minimal critical region for PWS-like phenotype (obesity, developmental delay with or without hypotonia and/or short extremities) to a 1-Mb region within the previously reported 4.1-Mb minimal region, 13 from nt 100 382 250 bp to nt 101 346 495 bp on Human Feb. 2009 (GRCh37/hg19) Assembly. This region contains the SIM1, MCHR2, and ASCC3 genes.…”

“…45 Thus, to date, although there is no strong evidence supporting an imprinting mechanism in the 6q16 region, a parent-of-origin effect cannot be excluded, as none of the three maternally derived deletions, which were currently reported, (patient no. 11, 14, and case 4 from Bonaglia et al report) 13 was associated with PWS-like features.…”

“…3, However, few of them underwent molecular characterisation of their genetic abnormalities, using either chromosomal microarray analysis, 3,13,[15][16][17][18]22,23,25 fluorescence in situ hybridisation (FISH) analysis with bacterial artificial chromosomes (BAC) clones 21 or STR analysis. 24 Two publications evaluated genotype-phenotype correlations at the 6q16 locus, but included only five and three patients, respectively.…”

“…24 Two publications evaluated genotype-phenotype correlations at the 6q16 locus, but included only five and three patients, respectively. 13,17 The first study identified a 4.1-Mb minimal critical region for PWS-like within the 6q16 cytogenetic band. 13 Recently, obesity and PWS-like syndrome have been ascribed to loss-of-function variants in the single-minded 1 (SIM1) gene encompassed in 6q16 critical minimal region, [37][38][39][40] whereas a role for GRIK2 deletion in behavioural problems has been suggested.…”

“…13 Recently, obesity and PWS-like syndrome have been ascribed to loss-of-function variants in the single-minded 1 (SIM1) gene encompassed in 6q16 critical minimal region, [37][38][39][40] whereas a role for GRIK2 deletion in behavioural problems has been suggested. 13 Here, we describe 15 new patients (including one fetus) with 6q16 deletions, including 6q16.2 and/or 6q16.3 sub-bands, investigated by chromosomal microarray analysis. Genotype-phenotype correlations were assessed.…”