Genetical, clinical, and functional analysis of a large international cohort of patients with autosomal recessive congenital ichthyosis due to mutations in NIPAL4

Abstract

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa-Like Domain-Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. OneThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.*Nadja Ballin and Alrun Hotz contributed equally to this work. patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype-phenotype correlations. K E Y W O R D SARCI, ARCI EM type III, collodion baby, ichthyosis, NIPAL4

Next‐generation sequencing through multi‐gene panel testing for diagnosis of hereditary ichthyosis in Chinese

“…It is worth noting that the limited number of ARCIs fails to reflect the truthful distribution of pathogenic genes causing ARCI in Chinese. For example, NIPAL4 gene was shown to be the second most commonly mutated gene in ARCI after TGM1 . However, in our study, TGM1 and NIPAL4 were not most common affected genes.…”

Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis

“…In most cases of ARCI, infants are born with a collodion membrane. Over the last decade at least ten different genes have been implicated in the etiology of ARCI [ 29 , 30 ]. All of these genes encode proteins that are involved in the formation of the cornified lipid envelope in the stratum corneum and ceramide formation and processing in the epidermis [ 49 ].…”

“…So far, 34 disease‐causing mutations have been reported in NIPAL4 including the highly recurrent mutation c.527C>A, p.(Ala176Asp) which is a possible hot spot [ 29 , 34 , 53 – 57 ]. Recently, a large international cohort of 101 families affected with ARCI carrying mutations in NIPAL4 was reported, among them 25 families were from Morocco, Algeria and Tunisia and 7 families were from Turkey and Syria [ 29 ].…”

“…So far, 34 disease‐causing mutations have been reported in NIPAL4 including the highly recurrent mutation c.527C>A, p.(Ala176Asp) which is a possible hot spot [ 29 , 34 , 53 – 57 ]. Recently, a large international cohort of 101 families affected with ARCI carrying mutations in NIPAL4 was reported, among them 25 families were from Morocco, Algeria and Tunisia and 7 families were from Turkey and Syria [ 29 ]. This report in accordance with previous studies suggest that ARCI phenotype associated with NIPAL4 is relatively frequent in the Mediterranean basin particularly in North Africa probably in relation with the high rate of consanguinity in those populations [ 58 ].…”

“…Among all potential pathogenic variants identified in the current datasets, we mainly focused on variants in known causative genes involved in Autosomal Recessive Congenital Ichthyosis (ARCI) based on the clinical overlapping features with the proband’s phenotype, those related to EKVP based on the phenotypic heterogeneity of the erythrokeratodermias, as well as, genes associated with the differential diagnosis of EKVP based on the previously cases reports [ 12 , 29 – 32 ].…”