High TGM1 Allelic Heterogeneity causing Lamellar ichthyosis in a small geographic area in South Mexico: Another Example of the "Réunion Paradox"

O F Chacon-Camacho; M C Astiazarán; G Vera-Duarte; H Gutiérrez-Múgica; N Macriz-Romero; E O Graue-Hernandez; J C Zenteno

doi:10.1016/j.ejmg.2023.104842

High TGM1 Allelic Heterogeneity causing Lamellar ichthyosis in a small geographic area in South Mexico: Another Example of the "Réunion Paradox"

Eur J Med Genet. 2023 Oct;66(10):104842. doi: 10.1016/j.ejmg.2023.104842. Epub 2023 Sep 12.

Authors

O F Chacon-Camacho¹, M C Astiazarán², G Vera-Duarte³, H Gutiérrez-Múgica⁴, N Macriz-Romero³, E O Graue-Hernandez³, J C Zenteno⁵

Affiliations

¹ Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico; Laboratorio 5 Edificio A-4, Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico.
² Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico.
³ Department of Cornea, Institute of Ophthalmology "Conde de Valenciana", Mexico.
⁴ Hospital Angeles, Clínica Londres, Mexico.
⁵ Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico; Biochemistry Department, Faculty Medicine, National Autonomous University of Mexico, Mexico City, Mexico; Rare Diseases Diagnostic Unit, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico. Electronic address: jczenteno@institutodeoftalmologia.org.

PMID: 37709012
DOI: 10.1016/j.ejmg.2023.104842

Abstract

Lamellar ichthyosis (LI) is an autosomal recessive congenital ichthyosis characterized by generalized dry skin and severe scaling. It is caused by biallelic mutations in the TGM1 gene, however molecular data from non-Caucasian populations are limited. Results of genetic-molecular analysis of a group of LI pedigrees originating from two close small populations from south Mexico are presented. LI affected individuals belonging to 9 apparently unrelated families were studied. Exome sequencing or Sanger sequencing in probands from each family was carried out. Furthermore, DNA from 294 unaffected subjects from one of the communities were Sanger sequenced to determine the carrier frequency of the c.427C > T TGM1 variant. Five different TGM1 pathogenic variants, either in homozygous or in compound heterozygous state, were demonstrated in affected subjects. The two most common variants were c.427C > T (p.Arg143Cys) and c.1159+1G > T. A novel c.1645+1G > T TGM1 pathogenic allele was recognized. Carrier frequency analysis identified a total of 23 individuals heterozygous for the c.427C > T variant, predicting a prevalence of 78 carriers per 1000 inhabitants in the community. A high TGM1 allelic heterogeneity with 5 different LI-causing alleles in a limited geographic area was demonstrated. While the occurrence of homozygosity for a founder mutation is expected in small populations with high frequency of a particular autosomal recessive disorder, the occurrence of multiple pathogenic alleles has been previously described, a situation known as the Reúnion paradox. Our results expand the current knowledge of the mutational spectrum of TGM1-linked LI.

Keywords: Ichthyosis; Lamellar ichthyosis; Mutation; TGM1; WES.