Awarded a one-year, $19,950 grant from Pachyonychia Congenita Project.
Pachyonychia congenita and palmoplantar disorders are rare, painful, and inherited skin and nail disorders. We intend to employ advanced genetic testing methods on several affected families from diverse Pakistani ethnicities with these disorders in order to find the specific faulty genes responsible for these conditions. We hope to discover new genes that have not been linked to these disorders before. The ultimate goal is to use these discoveries to improve diagnosis and develop better treatments for patients with these disorders.
Project Title: Genetic Elucidation of Inherited Pachyonychia Congenita and Palmoplantar Disorders Segregating in
Inbred Families: Insights into Disease Pathogenicity
Principal Investigator (PI) Name: Sajid Malik
PI Affiliations: Human Genetics Program, Department of Zoology, Quaid-i-Azam University, Islamabad
Abstract
Background: Pachyonychia Congenita (PC; OMIM 167200) and related Palmoplantar Disorders (PD; OMIM 144200) are rare, painful, and debilitating keratinization disorders characterized by nail dystrophy, palmoplantar keratoderma, leukokeratosis, and variable ectodermal features. These majorly dominantly inherited conditions severely affect quality of life, yet effective therapeutic options remain limited due to incomplete understanding of their molecular basis.
Aims: This proposed project aims to elucidate the genetic underpinnings of inherited PC and PD in Pakistani families, where the high rate of consanguinity and unique genetic diversity offer a valuable opportunity to uncover novel gene(s) and/or disease-causing variants. Pakistani families remain underrepresented in the international research scenario of PC and PD related disorders.
Methods: To date, five multigenerational families from diverse ethnicities presenting with characteristic phenotypes have been recruited, and detailed clinical data, including pedigrees and phenotypic variability, have been documented. DNA samples of affected and unaffected individuals are available. Using whole exome sequencing (WES), we intend to identify rare and potentially pathogenic gene(s)/variants segregating with the disorders within these families. Particular attention will be given to the detection of recessive variants, which are expected to be enriched due to consanguineous nature of families. Identified gene(s)/variants will subsequently undergo molecular and functional characterization through in vitro and in vivo assays, including expression studies in relevant cell line models.
Expected outcome: Given the remarkable ethnic diversity in Pakistani population, there is high likelihood to identify novel variants in known genes or novel genes. By integrating clinical and molecular findings, this study aims to expand the spectrum of known PC- and PD-associated genes, delineate novel genotype–phenotype correlations, and enhance the understanding of disease pathogenesis. Ultimately, these insights will pave the way for the development of improved diagnostic strategies and therapeutic interventions for these debilitating skin disorders.
