G Turner

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Non-specific X linked mental retardation.

Non-specific X linked mental retardation (MRX) is mental retardation in persons of normal physical appearance who have no recognisable features apart from a characteristic pedigree. Review of published reports shows that there is clinical variability in the degree of mental retardation within families and genetic heterogeneity, based on gene localisation, between families. We propose a classification based on genetic localisation and a set of minimal clinical features that should be recorded in the hope of identifying possible specific phenotypes.

Three new families with X-linked mental retardation caused by the 428–451dup(24bp) mutation in ARX

Three families with X‐linked mental retardation caused by a 24 base‐pair duplication in ARX[428–451dup(24u2003bp)] are reported. The clinical features in these and six other published families are reviewed. In general, the clinical picture is variable. Mental retardation ranges from mild to severe. Infantile spasms (West syndrome) occurred in 12.5% and other less severe forms of seizures in 37.5%. Characteristic dystonic movements of the hands were seen in 63% and dysarthria in 54%. The focal dystonia, in association with mental retardation, may prove to be diagnostic of this mutation.

Localisation of the MRX3 gene for non-specific X linked mental retardation.

A family is described with five affected males segregating a new gene for non-specific X linked mental retardation (MRX). Linkage analysis localised the gene at Xq28-qter. The maximum lod score was 2.89 with DXS52 (St14) at theta = 0.0. A recombinant was observed with DXS304 (U6.2) defining the proximal limit to the localisation. No evidence for linkage was determined using markers at several points along the remainder of the X chromosome, including the regions known to contain MRX1 and MRX2. This delineates the third gene for non-specific X linked mental retardation, MRX3.

Mutation screening in Börjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient

Background: Börjeson-Forssman-Lehmann syndrome (BFLS; MIM 301900) is an infrequently described X linked disorder caused by mutations in PHF6, a novel zinc finger gene of unknown function. Objective: To present the results of mutation screening in individuals referred for PHF6 testing and discuss the value of prior X-inactivation testing in the mothers of these individuals. Results: 25 unrelated individuals were screened (24 male, one female). Five PHF6 mutations were detected, two of which (c.940A→G and c.27_28insA) were novel. One of these new mutations, c.27_28insA, was identified in a female BFLS patient. This was shown to be a de novo mutation arising on the paternal chromosome. This is the first report of a clinically diagnosed BFLS female with a confirmed PHF6 mutation. In addition, the X-inactivation status of the mothers of 19 males with suggested clinical diagnosis of BFLS was determined. Skewed (⩾70%) X-inactivation was present in five mothers, three of whom had sons in whom a PHF6 mutation was detected. The mutation positive female also showed skewing. Conclusions: The results indicate that the success of PHF6 screening in males suspected of having BFLS is markedly increased if there is a positive family history and/or skewed X-inactivation is found in the mother.