Homozygosity haplotype and whole-exome sequencing analysis to identify potentially functional rare variants involved in multiple sclerosis among sardinian families

Teresa Fazia, Daria Marzanati, Anna Laura Carotenuto, Ashley Beecham, Athena Hadjixenofontos, Jacob L McCauley, Valeria Saddi, Marialuisa Piras, Luisa Bernardinelli, Davide Gentilini

Research output: Contribution to journalArticlepeer-review

Abstract

Multiple Sclerosis (MS) is a complex multifactorial autoimmune disease, whose sex-and age-adjusted prevalence in Sardinia (Italy) is among the highest worldwide. To date, 233 loci were associated with MS and almost 20% of risk heritability is attributable to common genetic variants, but many low-frequency and rare variants remain to be discovered. Here, we aimed to contribute to the understanding of the genetic basis of MS by investigating potentially functional rare variants. To this end, we analyzed thirteen multiplex Sardinian families with Immunochip genotyping data. For five families, Whole Exome Sequencing (WES) data were also available. Firstly, we performed a nonparametric Homozygosity Haplotype analysis for identifying the Region from Common Ancestor (RCA). Then, on these potential disease-linked RCA, we searched for the presence of rare variants shared by the affected individuals by analyzing WES data. We found: (i) a variant (43181034 T > G) in the splicing region on exon 27 of CUL9; (ii) a variant (50245517 A > C) in the splicing region on exon 16 of ATP9A; (iii) a non-synonymous variant (43223539 A > C), on exon 9 of TTBK1; (iv) a nonsynonymous variant (42976917 A > C) on exon 9 of PPP2R5D; and v) a variant (109859349-109859354) in 3UTR of MYO16.

Original languageEnglish (US)
Pages (from-to)1778-1793
Number of pages16
JournalCurrent Issues in Molecular Biology
Volume43
Issue number3
DOIs
StatePublished - Dec 2021

Keywords

  • Homozygosity Haplotype analysis
  • Low-frequency variants
  • Multiple sclerosis
  • Multiplex families
  • Rare variants
  • Region form Common Ancestor (RCA)
  • Sardinian population
  • WES data

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology
  • Microbiology (medical)

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