Received: 8 August 2017 Revised: 14 November 2017 Accepted: 26 December 2017 DOI: 10.1111/ahg.12244 SHORT COMMUNICATION A novel homozygous missense variant in NECTIN4 (PVRL4) causing ectodermal dysplasia cutaneous syndactyly syndrome Farooq Ahmad 1,2 Abdul Nasir 1 Holger Thiele 3 Muhammad Umair 1 Guntram Borck 2 Wasim Ahmad 1 1 Department of Biochemistry, Faculty of Bio- logical Sciences, Quaid-i-Azam University, Islamabad, Pakistan 2 Institute of Human Genetics, University of Ulm, Ulm, Germany 3 Cologne Center for Genomics (CCG), Uni- versity of Cologne, Cologne, Germany Correspondence Wasim Ahmad, PhD, Department of Biochem- istry, Faculty of Biological Sciences, Quaid-i- Azam University, Islamabad, Pakistan. Email: wahmad@qau.edu.pk Guntram Borck, MD, PhD, Institute of Human Genetics, University of Ulm, Albert-Einstein- Allee 11, 89081 Ulm, Germany. Email: guntram.borck@uni-ulm.de Funding information This work was supported by a grant from the Higher Education Commission (HEC), Islam- abad, Pakistan. FA was supported by the HEC- sponsored International Research Support Initiative Program (IRSIP). Abstract Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare form of ectodermal dysplasia including anomalies of hair, nails, and teeth along with bilateral cutaneous syndactyly of hands and feet. In the present report, we performed a clinical and genetic characterization of a consanguineous Pakistani family with four individuals affected by EDSS1. We performed exome sequencing using DNA of one affected individual. Exome data analysis identified a novel homozygous missense variant (c.242T>C; p.(Leu81Pro)) in NECTIN4 (PVRL4). Sanger sequencing validated this variant and confirmed its cosegregation with the disease phenotype in the family members. Thus, our report adds a novel variant to the NECTIN4 mutation spectrum and contributes to the NECTIN4-related clinical characterization. KEYWORDS consanguinity, ectodermal dysplasia syndactyly syndrome 1, EDSS1, homozygous, mutation, NECTIN4 1 INTRODUCTION Ectodermal dysplasias (EDs) present a large clinically and genetically heterogeneous group of congenital developmen- tal dystrophies of ectodermal derived appendages including hair, nails, teeth, and sweat glands. More than 200 clini- cally distinct conditions of EDs and ED syndromes have been described, with an estimated cumulative incidence rate of 7 in 10,000 births (Itin & Fistarol, 2004). Isolated and syndromic forms of EDs are characterized by particular clinical hallmarks. Mutations in cell–cell adhe- sion molecule-encoding genes have been reported as the cause of ED syndromes such as human juvenile macular dystrophy (HJMD; OMIM#601553) caused by mutations in the CDH3 gene (Ahmad et al., 2016), characterized by hypotrichosis followed by progressive degeneration of the central retina leading to blindness; and cleft lip/palate ED (CLPED1; OMIM#225060) and ED syndactyly syndrome (EDSS1; OMIM#613573) due to mutations in NECTIN1 (pre- viously known as PVRL1) and NECTIN4 (previously known as PVRL4), respectively (Brancati et al., 2010; Suzuki et al., 2000). EDSS1 is characterized by bilateral partial cutaneous syndactyly of the hands and feet, sparse to absent scalp hair and eyebrows and eyelashes, abnormal dentition (i.e., peg- shaped and conical crowns and early tooth loss), hypoplas- tic nails and palmoplantar keratoderma; whereas facial and dental anomalies, hypotrichosis, palmoplantar hyperkeratosis, dysplastic nails, syndactyly, and cleft lip/cleft palate are seen in CLPED1. Only 7 NECTIN4 mutations have thus far been described in EDSS1; thus, no clear-cut genotype-phenotype correlations have yet been described. In the present study, we describe a large consanguineous family of Pakistani origin displaying clinical features of EDSS1. We identified a novel homozygous NECTIN4 mis- sense variant (c.242T>C, p.(Leu81Pro)) segregating with the disease. Ann Hum Genet. 2018;1–7. © 2018 John Wiley & Sons Ltd/University College London 1 wileyonlinelibrary.com/journal/ahg