An autosomal recessive syndrome of severe mental retardation, cataract, coloboma and kyphosis maps to the pericentromeric region of chromosome 4

Abstract

We report on three siblings with a novel mental retardation (MR) syndrome who were born to distantly related Iranian parents. The clinical problems comprised severe MR, cataracts with onset in late adolescence, kyphosis, contractures of large joints, bulbous nose with broad nasal bridge, and thick lips. Two patients also had uni- or bilateral iris coloboma. Linkage analysis revealed a single 10.4 Mb interval of homozygosity with significant LOD score in the pericentromeric region of chromosome 4 flanked by SNPs rs728293 (4p12) and rs1105434 (4q12). This interval contains more than 40 genes, none of which has been implicated in MR so far. The identification of the causative gene defect for this syndrome will provide new insights into the development of the brain and the eye.

Figure 1

(a–c) Facial features of patients II:2 (a), II:3 (b) and II:4 (c). Note bulbous nose, broad nasal bridge and thick lips in all patients; and a large haemangioma on the left cheek of patient II:2 (a); and bilateral iris coloboma in patient II:4 (c). (d) Patient II:2. Note kyphosis and contractures of elbows and knees.

Figure 2

(a) Pedigree of the family and haplotypes of the linkage interval on chromosome 4. (b and c) Results of the parametric (b) and non-parametric (c) linkage analyses using the Merlin software. Both analyses revealed a single linkage interval in the pericentromeric region of chromosome 4, with LOD scores of 3.38 (parametric analysis) and 4.53 (non-parametric analysis) assuming third-cousin relationship of the parents.