Maternal uniparental isodisomy and heterodisomy on chromosome 6 encompassing a CUL7 gene mutation causing 3M syndrome

Abstract

We report a case of segmental uniparental maternal hetero- and isodisomy involving the whole of chromosome 6 (mat-hUPD6 and mat-iUPD6) and a cullin 7 (CUL7) gene mutation in a Japanese patient with 3M syndrome. 3M syndrome is a rare autosomal recessive disorder characterized by severe pre- and postnatal growth retardation that was recently reported to involve mutations in the CUL7 or obscurin-like 1 (OBSL1) genes. We encountered a patient with severe growth retardation, an inverted triangular gloomy face, an inverted triangle-shaped head, slender long bones, inguinal hernia, hydrocele testis, mild ventricular enlargement, and mild mental retardation. Sequence analysis of the CUL7 gene of the patient revealed a homozygous missense mutation, c.2975G>C. Genotype analysis using a single nucleotide polymorphism array revealed two mat-hUPD and two mat-iUPD regions involving the whole of chromosome 6 and encompassing CUL7. 3M syndrome caused by complete paternal iUPD of chromosome 6 involving a CUL7 mutation has been reported, but there have been no reports describing 3M syndrome with maternal UPD of chromosome 6. Our results represent a combination of iUPDs and hUPDs from maternal chromosome 6 involving a CUL7 mutation causing 3M syndrome.

Segmental Maternal UPD6 with Prenatal Growth Restriction

“…Of the 8 cases of maternal UPD6 previously reported [Sasaki et al, 2011], 5 had maternal isoUPD6, 2 had maternal heteroUPD6 and 1 had areas of both. Interestingly, only the patients with maternal isoUPD6 had IUGR (with 5 of 6 affected).…”

“…Four of the above 6 cases had maternal isoUPD6 of the entire chromosome. One [Sasaki et al, 2011] had maternal isoUPD6 in 2 regions (1 on each arm of chromosome 6, including 6q25.1q27). The other [Gümüş et al, 2010] had maternal isoUPD6 affecting part of the short arm, as well as UPD6 of 6q13q22.31 (the parent of origin of this region was not investigated by the authors).…”

“…As well as disordered imprinting, this may result in a child inheriting a homozygous mutation from a heterozygous parent, and thus being affected by a recessive condition of which only 1 parent is a carrier. At least 4 recessive conditions have been reported as a result of isoUPD of chromosome 6: 3M syndrome [Sasaki et al, 2011], C4 deficiency [Welch et al, 1990], molybdenum cofactor deficiency [Gümüş et al, 2010] and congenital adrenal hyperplasia [Spiro et al, 1999;Parker et al, 2006]. isoUPD may be segmental or it may involve the whole chromosome.…”

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

“…Height SDSs were calculated from 36 mutation-positive 3-M syndrome patients; 15 with CUL7 mutations, 15 with OBSL1 mutations and six with CCDC8 mutations. Height data were collected from our own clinics and from the published literature (Akawi et al 2011, Sasaki et al 2011.…”

“…Height data were collected from our own clinics, including patients in this study, from those we have previously reported (Hanson et al 2009(Hanson et al , 2011 and from the published literature (Akawi et al 2011, Sasaki et al 2011. Height SDSs were calculated from 36 mutation-positive 3-M syndrome patients, 15 with CUL7 mutations, 15 with OBSL1 mutations and six with CCDC8 mutations.…”