Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

Abstract

6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.

Figure 1

Fetopathological study of patient no. 1. (a) Facial features: short straight forehead, marked suborbital folds, broad nasal bridge, prominent philtrum, thin upper lip, micrognathia, and abnormally hemmed ears with a small horizontal fold along the upper edge of the helix. (b) Radiographs of the feet: bilateral calcaneal fragmentation and hypermineralisation. (c) Sagittal section through the brain: internal capsule dysmorphism with fusion of anterior caudate nucleus and putamen (black arrows). (d) Cerebral white matter containing ectopic neurons (black arrows). (e) Cerebellar grey matter containing ectopic neurons (black arrows). (f) Sagittal section through the cerebellum showing focal neuronal ectopia.

Figure 2

Photographs of four study patients. Note the round face, full cheeks, bulbous nose, and a prominent philtrum in patient no. 2; horizontal eyebrows and a prominent philtrum in patient no. 5; round face and full cheeks in patient no. 7; and a triangular face shape in patient no. 14.

Figure 3

Schematic alignment of 6q16 deletions obtained using Database of genomic Variants (DGV) Custom Tracks tool (http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg19/). (a) Representation of molecularly defined 6q16 deletions encompassing 6q16.2 and/or 6q16.3 sub-bands, reported here (red bars) or previously (grey bars). Previously reported deletions were characterised by DNA microarray,^{, , , , , , , ,} FISH analysis using BAC clones, or STR analysis. *Fetal case, **overweight, ***only perinatal data were available. (b) Enlargement of the minimal critical region defined by PWS-like patients, excluding patient no. 15 from the present series and Subject 11 from Rosenfeld et al series. The region contains three genes: MCHR2, SIM1, and ASCC3.