Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP

Background: Nonphotosensitive trichothiodystrophy (TTDN) is a rare autosomal recessive disorder of neuroectodermal origin. The condition is marked by hair abnormalities, intellectual impairment, nail dystrophies and susceptibility to infections but with no UV sensitivity. Methods: We identified three consanguineous Pakistani families with varied TTDN features and used homozygosity mapping, linkage analysis, and Sanger and exome sequencing in order to identify pathogenic variants. Haplotype analysis was performed and haplotype age estimated. A splicing assay was used to validate the effect of the MPLKIP splice variant on expression. Results: Affected individuals from all families exhibit several TTDN features along with a heart-specific feature, i.e. mitral regurgitation. Exome sequencing in the probands from families ED168 and ED241 identified a homozygous splice mutation c.339 + 1G > A within MPLKIP. The same splice variant co-segregates with TTDN in a third family ED210. The MPLKIP splice variant was not found in public databases, e.g. the Exome Aggregation Consortium, and in unrelated Pakistani controls. Functional analysis of the splice variant confirmed intron retention, which leads to protein truncation and loss of a phosphorylation site. Haplotype analysis identified a 585.1-kb haplotype which includes the MPLKIP variant, supporting the existence of a founder haplotype that is estimated to be 25,900 years old. Conclusion: This study extends the allelic and phenotypic spectra of MPLKIP-related TTDN, to include a splice variant that causes cardiomyopathy as part of the TTDN phenotype

Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly

<p>Abstract</p> <p>Background</p> <p>Autosomal Recessive Primary Microcephaly (MCPH) is a disorder of neurogenic mitosis. MCPH leads to reduced cerebral cortical volume and hence, reduced head circumference associated with mental retardation of variable degree. Genetic heterogeneity is well documented in patients with MCPH with six loci known, while pathogenic sequence variants in four respective genes have been identified so far. Mutations in <it>CDK5RAP2 </it>gene at MCPH3 locus have been least involved in causing MCPH phenotype.</p> <p>Methods</p> <p>All coding exons and exon/intron splice junctions of <it>CDK5RAP2 </it>gene were sequenced in affected and normal individuals of Pakistani MCPH family of Kashmiri origin, which showed linkage to MCPH3 locus on chromosome 9q33.2.</p> <p>Results</p> <p>A previously described nonsense mutation [243 T>A (S81X)] in exon 4 of <it>CDK5RAP2 </it>gene has been identified in the Pakistani family, presented here, with MCPH Phenotype. Genomic and cDNA sequence comparison revealed that the exact nomenclature for this mutation is 246 T>A (Y82X).</p> <p>Conclusion</p> <p>Recurrent observation of Y82X mutation in <it>CDK5RAP2 </it>gene in this Pakistani family may be a sign of confinement of a rare ancestral haplotype carrying this pathogenic variant within Northern Pakistani population, as this has not been reported in any other population.</p

Self-reported health and smoking status, and body mass index: a case-control comparison based on GEN SCRIP (GENetics of SChizophRenia In Pakistan) data

Introduction Individuals with schizophrenia are at a high risk of physical health comorbidities and premature mortality. Cardiovascular and metabolic causes are an important contributor. There are gaps in monitoring, documenting and managing these physical health comorbidities. Because of their condition, patients themselves may not be aware of these comorbidities and may not be able to follow a lifestyle that prevents and manages the complications. In many low-income and middle-income countries including Pakistan, the bulk of the burden of care for those struggling with schizophrenia falls on the families.Objectives To determine the rate of self-reported physical health disorders and risk factors, like body mass index (BMI) and smoking, associated with cardiovascular and metabolic disorders in cases of schizophrenia compared with a group of mentally healthy controls.Design A case-controlled, cross-sectional multicentre study of patients with schizophrenia in Pakistan.Settings Multiple data collection sites across the country for patients, that is, public and private psychiatric OPDs (out patient departments), specialised psychiatric care facilities, and psychiatric wards of teaching and district level hospitals. Healthy controls were enrolled from the community.Participants We report a total of 6838 participants’ data with (N 3411 (49.9%)) cases of schizophrenia compared with a group of healthy controls (N 3427 (50.1%)).Results BMI (OR 0.98 (CI 0.97 to 0.99), p=0.0025), and the rate of smoking is higher in patients with schizophrenia than in controls. Problems with vision (OR 0.13 (0.08 to 0.2), joint pain (OR 0.18 (0.07 to 0.44)) and high cholesterol (OR 0.13 (0.05 to 0.35)) have higher reported prevalence in controls. The cases describe more physical health disorders in the category ‘other’ (OR 4.65 (3.01 to 7.18)). This captures residual disorders not listed in the questionnaire.Conclusions Participants with schizophrenia in comparison with controls report more disorders. The access in the ‘other’ category may be a reflection of undiagnosed disorders