Acta Dermato-Venereologica 99-10CompleteContent | Page 14

894 INVESTIGATIVE REPORT Novel and Recurrent PNPLA1 Mutations in Spanish Patients with Autosomal Recessive Congenital Ichthyosis; Evidence of a Founder Effect Uxia ESPERÓN-MOLDES 1,2 , Manuel GINARTE VAL 3 , Laura RODRÍGUEZ-PAZOS 4 , Laura FACHAL 1 , José Manuel AZAÑA 5 , María Barberá FONS 6 , Mónica VIEJO DIAZ 7 and Ana VEGA 1 1 Galician Public Foundation of Genomic Medicine (FPGMX)-SERGAS, Genomics Medicine Group-USC, CIBERER, IDIS, 2 Department of Forensic Sciences, Pathological Anatomy, Gynecology, Obstetrics and Pediatrics, USC, 3 Dermatology Service of University Clinical Hospital of Santiago, Santiago de Compostela, 4 Dermatology Service of University Clinical Hospital of Vigo, Vigo, 5D ermatology Service of Albacete University Hospital Complex, Albacete, 6 Dermatology Service of University and Polytechnic Hospital La Fe, Valencia, and 7 Clinical Genetics Service of Central University Hospital of Asturias, Oviedo, Spain Autosomal recessive congenital ichthyosis is a group of rare non-syndrome diseases that affect cornifica- tion. PNPLA1 is one of the 12 related genes identified so far. Mutation screening of this gene has resulted in the identification of 13 individuals, from 10 fami- lies, who carried 7 different PNPLA1 mutations. These mutations included 2 missense, 2 frame­shift and 3 nonsense, 3 of them being novel. One of the identified variants, c.417_418delinsTC, was highly prevalent, as it was found in 6 out of 10 (60%) of our autosomal recessive congenital ichthyosis families with PNPLA1 mutations. Clinical manifestations varied significantly among patients, but altered sweating; erythema, pal- mar hyperlinearity and small whitish scales in flexor- extensor and facial areas were common symptoms. Haplotype analyses of c.417_418delinsTC carriers confirmed the existence of a common ancestor. This study expands the spectrum of the PNPLA1 disease, which causes variants and demonstrates that the c.417_418delinsTC mutation has founder effects in the Spanish population. Key words: ARCI; Spanish population; PNPLA1; founder effects; c.417_418delinsTC. Accepted May 22, 2019; E-published May 23, 2019 Acta Derm Venereol 2019; 99: 894–898. Corr: PhD Ana Vega, Molecular Medicine Service, Fundación Pública Ga- lega de Medicina Xenómica, University Hospital Santiago de Compostela, floor -2, Santiago de Compostela, Spain. E-mail: [email protected] N umerous hereditary cornification disorders that are clinically and aetiologically heterogeneous and follow a Mendelian inheritance pattern are grouped under the term of inherited ichthyosis. Autosomal re- cessive congenital ichthyosis (ARCI) are a subgroup of non-syndrome ichthyosis, whose phenotypic spectrum ranges from harlequin ichthyosis (HI; OMIM 242500), to less severe phenotypes such as congenital ichthyosi­ form erythroderma (CIE; OMIM 242100) or lamellar ichthyosis (LI; OMIM 242300) the last two being the most common phenotypes. To date, 12 genes have been implicated in the development of ARCI: ABCA12, doi: 10.2340/00015555-3227 Acta Derm Venereol 2019; 99: 894–898 SIGNIFICANCE Due to the growing importance of PNPLA1 mutations in the development of autosomal recessive congenital ichthyosis (ARCI), we decided to sequence this gene in a large, well- characterized cohort of Spanish ARCI patients. The muta- tional analysis revealed 7 different PNPLA1 mutations, 3 of which were novel, in 13 individuals from 10 families. Interestingly, one of the identified mutations was present in 60% of the families (c.417_418delinsTC; p.Ser140Pro). Haplotype analysis of the c.417_418delinsTC carriers de­ monstrated that these families are descendants of a recent founder who lived in the XI century, implying that this re- current mutation has founder effects in the Spanish popu- lation. ALOX12B, ALOXE3, CYP4F22, NIPAL4, TGM1, LIPN and more recently CERS3, PNPLA1, CASP14, SDR9C7 and SULT2B1 (1–3). PNPLA1 is a gene that encodes a 58 kDa protein involved in the glycerophospholipid metabolism of the cutaneous barrier. Forty-seven disease causing muta- tions have been described in PNPLA1 so far (4–12), the majority of which were reported within the last two years (4–9, 11, 12). Due to the growing importance of PNPLA1 mutations in the development of ARCI, we decided to screen for PNPLA1 defects in a large, well-characterized cohort of individuals with ARCI. Screening has resulted in the identification of a recur- rent variant, c.417_418delinsTC, which was present in approximately half of our families. Given the high prevalence of this mutation among our Spanish patients, we tested the hypothesis that this mutation arose in a founder ancestor in the distant past. Thus, the aims of this study are: (i) to report new cau- sative PNPLA1 mutations in a Spanish cohort of patients with ARCI, (ii) to computationally assess the effect of the recurrent c.417_418delinsTC mutation on protein function, (iii) to evaluate whether families who carry this variant share a common ancestor and, if so, (iv) to estimate the time to their most recent common ancestor (TMRCA) and the age of the mutation. This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.