A Recurrent Nonsense Mutation in NECTIN4 Underlying Ectodermal Dysplasia-Syndactyly Syndrome with a Novel Phenotype in a Consanguineous Kashmiri Family.

EDSS1, a syndrome characterized by ectodermal dysplasia-syndactyly, is inherited in an autosomal recessive manner due to mutations in the NECTIN4/PVRL4 gene. Clinical manifestations of the syndrome include defective nail plate, sparse to absent scalp and body hair, spaced teeth with enamel hypoplasia, and bilateral cutaneous syndactyly in the fingers and toes. Here, we report a consanguineous family of Kashmiri origin presenting features of EDSS1. Using whole exome sequencing, we found a recurrent nonsense mutation (NM_030916: c.181C > T, p.(Gln61 ∗)) in the NECTIN4 gene. The variant segregated perfectly with the disorder within the family. The candidate variant was absent in 50 in-house exomes pertaining to other disorders from the same population. In addition to the previously reported clinical phenotype, an upper lip cleft was found in one of the affected members as a novel phenotype that is not reported by previous studies in EDSS1 patients. Therefore, the study presented here, which was conducted on the Kashmiri population, is the first to document a NECTIN4 mutation associated with the upper lip cleft as a novel phenotype. This finding broadens the molecular and phenotypic spectrum of EDSS1.

Novel heterozygous sequence variant in the GLI1 underlies postaxial polydactyly.

Polydactyly is one of the most common congenital abnormal phenotype of autopod, which is characterized by extra supernumerary digit in hands/feet with or without well-developed bony structure within the digits. Preaxial polydactyly (PPD), postaxial polydactyly (PAP), and meso-axial (central) polydactyly are three different isoforms of polydactyly. Genetically, at least 10 genes have been identified causing nonsyndromic polydactyly. In the present study, we have investigated a large family segregating autosomal dominant form of nonsyndromic polydactyly. Whole exome sequencing followed by Sanger sequencing revealed a novel heterozygous missense variant (NM_005269.3; c.1064C>A; p.(Thr355Asn) in the gene GLI1 segregating with the disease phenotype within the family. This study presents first familial case of autosomal dominant form of polydactyly caused by the GLI1 variant.

Variants in GLI3 Cause Greig Cephalopolysyndactyly Syndrome.

Background: Greig cephalopolysyndactyly syndrome (GCPS) is a disorder of autopod and craniofacial abnormalities. Autopod anomalies include preaxial and/or postaxial polydactyly together with or without syndactyly while craniofacial features include hypertelorism and macrocephaly. GCPS is inherited in an autosomal dominant manner and is caused by sequence variants in GLI3. Methodology and Results: In this study, we examined four unrelated families with GCPS segregating in an autosomal dominant manner. Sanger sequencing revealed three novel (p.Tyr146Leufs*19, p.Glu99Serfs*60, and p.Thr541Arg) and one previously reported non-sense variant (p.Arg792*) in GLI3. Conclusion: The study expands the spectrum of the variants in the GLI3 gene linked to GCPS, and should also facilitate genetic counseling of GCPS patients in the Pakistani population.

Congenital atrichia with papular lesions resulting from novel mutations in human hairless gene in four consanguineous families.

Congenital atrichia with papular lesions (APL; Mendelian Inheritance in Man no. 209500) is a rare form of irreversible alopecia that follows an autosomal recessive mode of inheritance. Patients with this form of alopecia show hair loss soon after birth with the development of papular lesions of keratin-filled cysts over the body. Several studies have reported sequence variants in the human hairless (HR) gene as the underlying cause of this disorder. In the present study, we have reported four consanguineous families showing features of APL. Genotyping using microsatellite markers showed mapping of all four families to the hairless (HR) gene on chromosome 8p21.1. Further, DNA sequence analysis of the HR gene revealed three novel mutations including two nonsense (p.Cys690X, p.Arg819X) and a missense (p.Pro1157Arg) in the four families.

Breast and Ovarian Cancer Risk due to Prevalence of BRCA1 and BRCA2 Variants in Pakistani Population: A Pakistani Database Report.

Introduction. Pakistani population has a very rich anthrogeneological background with waves of migration from neighboring regions. Incidence rates of breast and ovarian cancer in Pakistan are on such a rapid rise that it is necessary to check the contributory factors, genetic and nongenetic. An insight into the prevalence data emphasizes the formulation of a BRCA1 and BRCA2 database for the Pakistani population. Method. In this study conducted by authors, data from diagnosed cases of both sporadic and inherited female breast and ovarian cancer cases was gathered after performing molecular genetic analysis by screening for alterations in the coding sequence of the BRCA gene. The region of interest was analyzed by the aid of various molecular biology tools such as automated DNA sequencer. Bioinformatics software was used to interpret the results, and database was prepared. Results. Mutational screening of the exons in all the samples of our study group did not reveal any pathogenic mutation. These results along with the results of the previous Pakistani studies for both BRCA1 and BRCA2 genes were summed up to prepare a Pakistani database. Percentage involvement of these genes was estimated. Nine percent of these cancers show alterations in BRCA1 gene while 3 percent have shown BRCA2 variants. The remaining 88 percent of breast and ovarian cancers can be attributed to the involvement of other genes.

Recurrent mutations in functionally-related EDA and EDAR genes underlie X-linked isolated hypodontia and autosomal recessive hypohidrotic ectodermal dysplasia.

Mutations in three functionally related genes EDA, EDAR and EDARDD have been reported to cause hypohidrotic ectodermal dysplasia (HED), which is characterized by sparse hair, reduced ability to sweat, and hypodontia. In few cases mutations in the EDA gene have been found to result in X-linked recessive isolated hypodontia. In the study, presented here, we have ascertained two large Pakistani families (A and B) with autosomal recessive form of hypohidrotic ectodermal dysplasia and X-linked recessive isolated hypodontia. Genetic mapping showed linkage of family A to EDAR gene on chromosome 2q11-q13 and family B to EDA gene on chromosome Xq12-q13.1. Subsequently, DNA sequencing of the coding regions of EDAR and EDA genes revealed previously described mutations. Sequence analysis identified a four base-pair splice-junction deletion mutation (c.718_721delAAAG) in EDAR gene in family A and a missense mutation (c.T1091C; p.M364T) in EDA gene in family B. Recurrence of mutations in EDAR and EDA genes in unrelated families is evocative of the dispersion of ancestral chromosome in different locality groups through common ancestors.