Seckel Syndrome 10

A number sign (#) is used with this entry because of evidence that Seckel syndrome-10 (SCKL10) is caused by compound heterozygous mutation in the NSMCE2 gene (617246) on chromosome 8q24.

For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see SCKL1 (210600).

Clinical Features

Payne et al. (2014) studied 2 unrelated 46,XX women with severe short stature and microcephaly; facial dysmorphism with small jaw and prominent midface; extremely insulin-resistant diabetes, fatty liver, and hypertriglyceridemia developing in childhood; and primary gonadal failure. One of the women was congenitally blind, reportedly due to retinal detachment, and died suddenly at age 33 years, presumably due to rupture of a previously documented abdominal aortic aneurysm.

Molecular Genetics

In a Welsh woman with severe short stature, microcephaly, insulin resistance, and primary gonadal failure, Payne et al. (2014) performed exome sequencing and identified compound heterozygosity for a 1-bp deletion (617246.0001) and a 4-bp insertion (617246.0002) in the NSMCE2 gene. In a similarly affected French woman, Sanger sequencing of NSMCE2 revealed compound heterozygosity for the same 2 mutations. The parents in both families were heterozygous for the mutations; haplotype analysis confirmed that both patients inherited the same rare 2 haplotypes within a region greater than 510 kb, suggesting shared common ancestral haplotypes. Neither of the mutations or haplotypes were found in a sample of 54 controls from Great Britain, in 4,190 internal control exomes and genomes, or in the 1000 Genomes Project database (July 2012); however, the 1-bp deletion was found in heterozygous state in 2 of 6,250 individuals in the NHLBI Exome Sequencing Project database (April 2013; allele frequency, 0.00016).