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Founder Effects in Hereditary Hemorrhagic Telangiectasia.

ABSTRACT: A founder effect can result from the establishment of a new population by individuals from a larger population or bottleneck events. Certain alleles may be found at much higher frequencies because of genetic drift immediately after the founder event. We provide a systematic literature review of the sporadically reported founder effects in hereditary hemorrhagic telangiectasia (HHT). All publications from the ACVRL1, ENG and SMAD4 Mutation Databases and publications searched for terms "hereditary hemorrhagic telangiectasia" and "founder" in PubMed and Scopus, respectively, were extracted. Following duplicate removal, 141 publications were searched for the terms "founder" and "founding" and the etymon "ancest". Finally, 67 publications between 1992 and 2020 were reviewed. Founder effects were graded upon shared area of ancestry/residence, shared core haplotypes, genealogy and prevalence. Twenty-six ACVRL1 and 12 ENG variants with a potential founder effect were identified. The bigger the cluster of families with a founder mutation, the more remarkable is its influence to the populational ACVRL1/ENG ratio, affecting HHT phenotype. Being aware of founder effects might simplify the diagnosis of HHT by establishing local genetic algorithms. Families sharing a common core haplotype might serve as a basis to study potential second-hits in the etiology of HHT.

SUBMITTER: Major T

PROVIDER: S-EPMC8070971 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeThe presence of malformations of cortical development in patients with hereditary hemorrhagic telangiectasia has been reported on previous occasions. We evaluated a sample of adults with hereditary hemorrhagic telangiectasia for the presence of malformations of cortical development, spatial coincidence of malformations of cortical development and AVMs, and the coincidence of brain and pulmonary AVMs.Materials and methodsA total of 141 patients 18 years of age or older who were referred to the Augusta University hereditary hemorrhagic telangiectasia clinic and underwent brain MR imaging between January 19, 2018, and December 3, 2020, were identified. MR imaging examinations were reviewed retrospectively by 2 experienced neuroradiologists, and the presence of malformations of cortical development and AVMs was confirmed by consensus. Demographic and clinical information was collected for each case, including age, sex, hereditary hemorrhagic telangiectasia status by the Curacao Criteria, mutation type, presence of malformations of cortical development, presence of brain AVMs, presence of pulmonary AVMs, and a history of seizures or learning disabilities.ResultsFive of 141 (3.5%) patients with hereditary hemorrhagic telangiectasia had malformations of cortical development. Two of the 5 patients with polymicrogyria also had closed-lip schizencephaly. One of the patients had a porencephalic cavity partially lined with heterotopic GM. The incidence of spatially coincident polymicrogyria and brain AVMs was 40% (2/5 cases). Of the patients with hereditary hemorrhagic telangiectasia and malformations of cortical development, 4/5 (80%) had pulmonary AVMs and 2/5 (40%) had brain AVMs.ConclusionsTo our knowledge, we are the first group to report the presence of schizencephaly in patients with hereditary hemorrhagic telangiectasia. The presence of schizencephaly and porencephaly lends support to the hypothesis of regional in utero cerebral hypoxic events as the etiology of malformations of cortical development in hereditary hemorrhagic telangiectasia.

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Founder Effects in Hereditary Hemorrhagic Telangiectasia.

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