One Disease with two Faces: Semidominant Inheritance of a Novel HTRA1 Mutation in a Consanguineous Family


Bekircan-Kurt C. E. , ÇETİNKAYA A., GÖÇMEN R., KOŞUKCU C., Soylemezoglu F., ARSAVA E. M. , ...More

JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, vol.30, no.9, 2021 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 30 Issue: 9
  • Publication Date: 2021
  • Doi Number: 10.1016/j.jstrokecerebrovasdis.2021.105997
  • Journal Name: JOURNAL OF STROKE & CEREBROVASCULAR DISEASES
  • Journal Indexes: Science Citation Index Expanded, Scopus, CINAHL, EMBASE, MEDLINE
  • Keywords: Cerebral small vessel disease, CARASIL, CADASIL type 2, HTRA1, AUTOSOMAL RECESSIVE ARTERIOPATHY, SUBCORTICAL INFARCTS, CARASIL, LEUKOENCEPHALOPATHY, GENE, CADASIL

Abstract

Objectives: To identify the underlying genetic defect for a consanguineous family with an unusually high number of members affected by cerebral small vessel disease. Materials and methods: A total of 6 individuals, of whom 3 are severely affected, from the family were clinically and radiologically evaluated. SNP genotyping was performed in multiple members to demonstrate genome-wide runs-of-homozygosity. Coding variants in the most likely candidate gene, HTRA1 were explored by Sanger sequencing. Published HTRA1-related phenotypes were extensively reviewed to explore the effect of number of affected alleles on phenotypic expression. Results: Genome-wide homozygosity mapping identified a 3.2 Mbp stretch on chromosome 10q26.3 where HTRA1 gene is located. HTRA1 sequencing revealed an evolutionarily conserved novel homozygous c.824C>T (p.Pro275Leu) mutation, affecting the serine protease domain of HtrA1. Early-onset of cognitive and motor deterioration in homozygotes are in consensus with CARASIL. However, there was a clear phenotypic variability between homozygotes which includes alopecia, a suggested hallmark of CARASIL. All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation. Conclusion: Here, we clearly demonstrate that CARASIL and CADASIL type 2 are two clinical consequences of the same disorder with different severities thorough the evaluation of the largest collection of homozygotes and heterozygotes segregating in a family. Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms.