Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3

Abstract

As part of a large-scale, systematic effort to unravel the molecular causes of autosomal recessive mental retardation, we have previously described a novel syndrome consisting of mental retardation, coloboma, cataract and kyphosis (Kahrizi syndrome, OMIM 612713) and mapped the underlying gene to a 10.4-Mb interval near the centromere on chromosome 4. By combining array-based exon enrichment and next generation sequencing, we have now identified a homozygous frameshift mutation (c.203dupC; p.Phe69LeufsX2) in the gene for steroid 5α-reductase type 3 (SRD5A3) as the disease-causing change in this interval. Recent evidence indicates that this enzyme is required for the conversion of polyprenol to dolichol, a step that is essential for N-linked protein glycosylation. Independently, another group has recently observed SRD5A3 mutations in several families with a type 1 congenital disorder of glycosylation (CDG type Ix, OMIM 212067), mental retardation, cerebellar ataxia and eye disorders. Our results show that Kahrizi syndrome and this CDG Ix subtype are allelic disorders, and they illustrate the potential of next-generation sequencing strategies for the elucidation of single gene defects.

Figure 1

(a) Graphical representation of the linkage interval in the pericentromeric region of chromosome 4 (red box), the position of SRD5A3, the position of the mutation and partial chromatogram of exon 1 of the index patient. The asterisk denotes the duplication of one cytosine (c.203dupC;p.Phe69LeufsX2). (b) Results of the RT-PCR using RNA derived from a lymphoblastoid cell line of the index patient showing absence (ex 1–4) or reduced (ex 4–5) expression of SRD5A3 transcripts. HUWE was used as an internal control. The color reproduction of the figure is available on the html full text version of the paper.