Biogeographical origin and timing of the founder ichthyosis TGM1 c.1187G > A mutation in an isolated Ecuadorian population

Abstract

An unusually high frequency of the lamellar ichthyosis TGM1 mutation, c.1187G > A, has been observed in the Ecuadorian province of Manabí. Recently, the same mutation has been detected in a Galician patient (Northwest of Spain). By analyzing patterns of genetic variation around this mutation in Ecuadorian patients and population matched controls, we were able to estimate the age of c.1187G > A and the time to their most recent common ancestor (TMRCA) of c.1187G > A Ecuadorian carriers. While the estimated mutation age is 41 generations ago (~1,025 years ago [ya]), the TMRCA of Ecuadorian c.1187G > A carrier haplotypes dates to just 17 generations (~425 ya). Probabilistic-based inferences of local ancestry allowed us to infer a most likely European origin of a few (16% to 30%) Ecuadorian haplotypes carrying this mutation. In addition, inferences on demographic historical changes based on c.1187G > A Ecuadorian carrier haplotypes estimated an exponential population growth starting ~20 generations, compatible with a recent founder effect occurring in Manabí. Two main hypotheses can be considered for the origin of c.1187G > A: ( i ) the mutation could have arisen in Spain >1,000 ya (being Galicia the possible homeland) and then carried to Ecuador by Spaniards in colonial times ~400 ya, and ( ii ) two independent mutational events originated this mutation in Ecuador and Galicia. The geographic and cultural characteristics of Manabí could have favored a founder effect that explains the high prevalence of TGM1 c.1187G > A in this region.

Increased risk of depression and impairment in quality of life in patients with lamellar ichthyosis

“…We carried out the determination of the clinical severity of LI according to the CISI, which covers the following variables: squamae (1-5), erythema (1)(2)(3)(4)(5)(6), and alopecia (1-5), the higher the CISI score, the greater the severity of the disease. 25 The DBI-II was used to determine the depression score; this tool implies 21 items with a score of 0-3 (No symptoms to symptoms strongly present).…”

“…Lamellar ichthyosis (LI) is a genetic skin disease characterized by thick plate‐like scales with distribution throughout the body, as well as itching, pain, inflammation, alopecia, and sometimes erythema 1,2 . The prevalence of LI in the general population varies according to the geographical zone between 1:200000 and 1:300000, 3,4 but it can be higher in specific regions due to the appearance of founder effects 5,6 . LI is one of the most severe clinical phenotypes of ichthyosis, behind harlequin ichthyosis, among the so‐called autosomal recessive congenital ichthyoses (ARCI) 7 …”

“…1,2 The prevalence of LI in the general population varies according to the geographical zone between 1:200000 and 1:300000, 3,4 but it can be higher in specific regions due to the appearance of founder effects. 5,6 LI is one of the most severe clinical phenotypes of ichthyosis, behind harlequin ichthyosis, among the so-called autosomal recessive congenital ichthyoses (ARCI). 7 The severe cutaneous manifestations in noticeable body parts of LI patients may produce them shame, low self-esteem, discrimination, and social isolation, which could lead to mental health disorders such as depression, as well as impairment in their quality of life (QoL).…”

Current Strategies for the Gene Therapy of Autosomal Recessive Congenital Ichthyosis and Other Types of Inherited Ichthyosis

“…However, the highest LI incidence rate is found in Norway (1:91,000) [ 15 ] and Galicia (northern Spain) (1:122,000) [ 12 ], with both cases being due to the founder effect. Presumably, the mutation in Galicia could have arisen about 1000 years ago and then spread to the Ecuadorian province of Manabí, where LI is also highly prevalent [ 16 ].…”

Molecular Genetic Study of Congenital Ichthyosiform Erythroderma (CIE) Reveals a Novel Likely Pathogenic Variant in an Iranian Pedigree

“…ARCI is divided into harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma (CIE) (2,3). The two latter conditions are at the extreme end of the ARCI spectrum, in which large dark cutaneous scales with negligible erythema are the characteristics of LI while erythroderma and white scales are more frequent in CIE patients (4).…”