Identification of novel locus at chromosome 3p12.3-q13.31 for autosomal recessive intellectual disability in a consanguineous family.

To the Editor : Intellectual disability (ID) is a common disability affecting 1–3% of the general population. ID is defined as having an IQ less than 70. ID can be divided into syndromic forms (SID) and non-syndromic forms (NSID). Whereas SID is characterized by malformations, dysmorphic features or neurological abnormalities, NSID is characterized by the presence of ID without any additional features (1). Searching for genes responsible for NSID has been difficult because of the absence of specific clinical criteria for grouping the NSID families, and due to the absence of large families with several affected members for linkage studies. However, in the recent years, with the help of new technologies like next generation sequencing (NGS), different genes causing autosomal recessive NSID have been identified, even in the absence of initial linkage studies (2). Table 1 shows autosomal dominant and recessive loci and genes for NSID identified to date. Here we report the identification of a novel locus for NSID. Using homozygosity mapping based on single nucleotide polymorphism (SNP) array of a large consanguineous family with several affected members, we have identified a 40.98 Mb locus on chromosome 3p12.3-q13.31 corresponding to positions 74.36–115.34 Mb, designated MRT35. Affected individuals from two branches of a Pakistani family with six affected children, all with mild to severe ID were investigated (Fig. 1a). Branch 1 had four affected children, two girls and two boys. One affected son of this branch (IV5) died of a brain tumor at age 17. Branch 2 has two affected sons. Parents in both branches are normal. The affected children all have NSID but the degree of retardation varies from moderate to severe. Affected children from branch 2 have a milder form of ID than affected members from branch 1, but variation also exists among members of the same branch. Thus, IV7 (branch 1) has a more severe form of ID than the other affected children from the same branch. The family was classified as having NSID even though the affected children have nystagmus, strabismus and late vision development, in addition to behavioral and learning difficulties, because many patients with ID have such anomalies (3). Examination of 586 children with NSID had previously shown that 78.7% had ocular or refractive findings, 2.7% had nystagmus and 12.1% had strabismus (3). Patient IV6 had a cerebral computed tomography (CT) scan at age 1 that showed a slight asymmetry but was otherwise normal. Cerebral CT in patient IV1 at age 1 was also normal. Congenital cytomegalovirus and toxoplasmosis infections were excluded in patient IV1 as well. Metabolic screening of urine was performed in IV7 (amino acids, organic acids and lysosomal enzymes) and IV6 (organic acids) with normal results, as was thyroid function in both individuals. In IV7, comparative genomic hybridization array and fragile X testing gave normal results. Pregnancy, birth and postnatal growth were normal in all patients, and no evidence of other environmental factors as a cause of ID, e.g. congenital infections, has been found. The pedigree points to an autosomal recessive mode of inheritance, and we assume that all the affected family members are homozygous for the same mutation. Genome-wide SNP microarray analysis was performed on genomic DNA from four affected and six unaffected individuals. The SNP genome scan revealed a 40.98 Mb homozygous region on chromosome 3 corresponding to positions 74.36–115.34 Mb (Hg19), which was the largest homozygous region. The four affected individuals, and none of the healthy individuals, were homozygous for all SNPs located in this region between rs663986 and rs2218054. No duplication or deletion was identified in the region by copy number analysis (chromosome analysis suite software; Affymetrix, Santa Clara, CA). Logarithm of the odds (LOD) score calculations showed a maximum multipoint LOD score of Z = 3.19 for this region, and no other region showed a LOD score above 3 (Fig. 1b). Further the rest of the genome was excluded by a LOD score of Z =−2. The locus contains around 180 different RefSeq genes and four known miRNAs (UCSC genome Browser hg19, http://genome.ucsc.edu). Some of the RefSeq genes are associated with SID, e.g. Joubert syndrome, but no known genes for NSID are located in the region, and the patients do not fit the clinical