Naveed Wasif

Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86.

Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.

A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2)

Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on scalp and rest of the body of affected subjects. Recently, three clinically similar autosomal recessive forms of hypotrichosis [localized autosomal recessive hypotrichosis (LAH)1], LAH2 and LAH3 have been mapped on chromosomes 18q12.1, 3q27.3, and 13q14.11‐q21.32, respectively. For these three loci, two genes DSG4 for LAH1 and LIPH for LAH2 have been identified. To date, only five mutations in DSG4 and two in LIPH genes have been reported. In this study, we have ascertained two large unrelated consanguineous Pakistani families with autosomal recessive form of hypotrichosis. Affected individuals showed homozygosity to the microsatellite markers tightly linked to LIPH gene on chromosome 3q27. Sequence analysis of the gene in the affected subjects from both the families revealed a novel deletion mutation in exon 5 (c.659‐660delTA) causing frameshift and downstream premature termination codon. All the three mutations identified in the LIPH gene, including the one in this study, are deletion mutations.

Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families.

Background  Autosomal recessive hypotrichosis is a rare genetic irreversible hair loss characterized by sparse scalp hair, sparse to absent eyebrows and eyelashes, and sparse axillary and body hair. Affected male individuals have normal beard hair.

Novel mutations in the keratin-74 (KRT74) gene underlie autosomal dominant woolly hair/hypotrichosis in Pakistani families

Autosomal dominant woolly hair (ADWH) is an inherited condition of tightly curled and twisted scalp hair. Recently, a mutation in human keratin-74 (KRT74) gene has been shown to cause this form of hereditary hair disorder. In the present study, we have described two families (A and B) having multiple individuals affected with autosomal dominant form of hair loss disorders. In family A, 10 individuals showed ADWH phenotype while in the family B, 14 individuals showed hypotrichosis of the scalp. Genotyping using polymorphic microsatellite markers showed linkage of both the families to type II keratin gene cluster on the chromosome 12q12-14.1. Mutation analysis of the KRT74 gene identified two novel mutations in the affected individuals of the families. The sequence analysis revealed a splice acceptor site mutation (c.IVS8-1G>A) in family A and a missense variant (c.1444G>A, p.Asp482Asn) in family B. Mutations identified in the present study extend the body of evidence implicating the KRT74 gene in the pathogenesis of autosomal dominant hair loss disorders.

A novel insertion mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene underlies Grebe-type chondrodysplasia in a consanguineous Pakistani family

BackgroundGrebe-type chondrodysplasia (GCD) is a rare autosomal recessive syndrome characterized by severe acromesomelic limb shortness with non-functional knob like fingers resembling toes. Mutations in the cartilage-derived morphogenetic protein 1 (CDMP1) gene cause Grebe-type chondrodysplasia.MethodsGenotyping of six members of a Pakistani family with Grebe-type chondrodysplasia, including two affected and four unaffected individuals, was carried out by using polymorphic microsatellite markers, which are closely linked to CDMP1 locus on chromosome 20q11.22. To screen for a mutation in CDMP1 gene, all of its coding exons and splice junction sites were PCR amplified from genomic DNA of affected and unaffected individuals of the family and sequenced directly in an ABI Prism 310 automated DNA sequencer.ResultsGenotyping results showed linkage of the family to CDMP1 locus. Sequence analysis of the CDMP1 gene identified a novel four bases insertion mutation (1114insGAGT) in exon 2 of the gene causing frameshift and premature termination of the polypeptide.ConclusionWe describe a 4 bp novel insertion mutation in CDMP1 gene in a Pakistani family with Grebe-type chondrodysplasia. Our findings extend the body of evidence that supports the importance of CDMP1 in the development of limbs.

Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A

Background Postaxial polydactyly (PAP) type A is characterised by well-formed functionally developed 5th digit duplication in hands and/or feet. It is genetically heterogeneous condition, inherited both in autosomal recessive and dominant manners. To date one autosomal recessive and four autosomal dominant loci have been mapped on human chromosomes. In the present study we have investigated a consanguineous Pakistani family segregating autosomal recessive PAP type A to identify the gene responsible for this phenotype. Methods Whole exome sequencing combined with homozygosity mapping and array comparative genomic hybridisation (aCGH) analysis was used to search for a genetic cause of PAP type A in the present study. Results Exome sequencing identified a missense mutation (c.1420C>T; p.Thr474Ile) in all the affected individuals of the family, in the gene ZNF141, mapped to the telomeric region on chromosome 4p16.3. Conclusion This study revealed involvement of a zinc finger gene ZNF141 in causing autosomal recessive PAP type A, which may open up interesting perspectives into the function of this protein in limb development.

Mutations in the LPAR6 and LIPH genes underlie autosomal recessive hypotrichosis/woolly hair in 17 consanguineous families from Pakistan

Background.  Autosomal recessive hypotrichosis/woolly hair is a rare genetic hair loss disorder characterized by sparse scalp hair/woolly hair, sparse to absent eyebrows and eyelashes, sparse axillary and body hair in affected individuals. This form of hair loss results from mutations in either LPAR6 or LIPH gene.

A novel deletion mutation in the EDAR gene in a Pakistani family with autosomal recessive hypohidrotic ectodermal dysplasia

with thrombosis in the presence of inflammation. Seven days later, the patient once again had a recurrence of the acute abdominal pain and fever of 38 C. As all the above treatments had failed to control the disease, IVIG (human immunoglobulin, PH4; Boya Biopharmaceutical Co., China) was administered for five consecutive days at a dosage of 0Æ4 g kg daily. Her condition soon improved, with neither new lesions nor abdominal pain developing. She was discharged in January 2006. Up to now, at 11 months of follow-up, her general health has remained good. Since the first case report in 1942, approximately 200 cases have been published of Degos disease. It is a disorder characterized by multiple infarcts in the skin and internal organs, related to a thrombotic vasculopathy of unknown origin. Clinically, in addition to the characteristic atrophic and porcelain white centred papules, involvement of the gastrointestinal tract is observed in 50% of cases, with intestinal perforation being the most common cause of death. These patients usually die in several months. Unfortunately, until now there has been no effective treatment for Degos disease. Most reported agents used are anticoagulants, antiplatelet agents, stimulators of fibrinolysis, immunosuppressants and corticosteroids, but not all cases respond to the therapy. Our patient had typical Degos disease with cutaneous and recurrent perforating intestinal lesions. We tried to treat her with warfarin, dipyridamole and prostaglandin E1 which has been reported to be effective in a Japanese patient with perforating intestinal Degos disease who achieved long-term survival. However, all these therapies proved to be unsuccessful. As our patient needed effective treatment to control the progression of her disease we felt that IVIG was a good option. The reported successful response to IVIG in patients with Kawasaki disease, which is a generalized vasculitis with possible thrombus of the involved vessels, supported our decision to use one course of high-dose IVIG therapy (0Æ4 g kg daily for 5 days). A week later a dramatic improvement of the lesions and general condition was noticed. During the following 11 months of follow-up, the patient has had no new skin lesions or gastrointestinal complaints. To our knowledge, IVIG has not previously been reported for use in patients with Degos disease. The beneficial consequences in our present patient with recurrent perforation of the intestines is encouraging, although the potential mechanism of action remains unknown.

A Novel Nonsense Mutation in RSPO4 Gene Underlies Autosomal Recessive Congenital Anonychia in a Pakistani Family

Abstract:  Congenital anonychia is an inherited autosomal recessive disorder characterized by complete absence of fingernails or toenails, or both. In the present study, we have described a consanguineous Pakistani family having a family member affected with congenital anonychia. Genotyping using polymorphic microsatellite markers showed linkage of the family to gene RSPO4 encoding R‐spondin and mapped on human chromosome 20p13. Deoxyribonucleic acid sequence analysis of the gene identified a novel nonsense mutation (c.18C>A; p.Cys6X) in the affected family member.

A novel missense mutation in the EVC gene underlies Ellis-van Creveld syndrome in a Pakistani family

Background:  Ellis‐van Creveld (EVC) syndrome is a rare autosomal recessive disorder characterized by skeletal, ectodermal and cardiac defects. This syndrome is caused by mutations in EVC and EVC2 genes, which are separated by 2.6 kb of genomic sequence on chromosome 4p16.