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Clinical features and pathogenicity assessment in patients with HTRA1-autosomal dominant disease

Zheng He1, Lijun Wang1, Yichi Zhang1

  • 1Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.

Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
|October 17, 2022
PubMed

Insights

Heterozygous mutations in HTRA1 cause autosomal dominant cerebral small vessel disease (AD-HTRA1). This study links the c.854C>T (p.P285L) HTRA1 mutation to early-onset cognitive impairment and associates mutation severity with white matter hyperintensity (WMH) progression.

Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • Heterozygous mutations in the HTRA1 gene are identified as a cause of autosomal dominant cerebral small vessel disease (AD-HTRA1).
  • AD-HTRA1 is recognized by European Academy of Neurology consensus recommendations.
  • This study investigates the clinical spectrum of an HTRA1 mutation and its impact on white matter hyperintensity (WMH).

Purpose of the Study:

  • To investigate the clinical features associated with a specific HTRA1 gene mutation.
  • To determine the effect of the HTRA1 mutation on the development and severity of white matter hyperintensities (WMH).
  • To evaluate the correlation between mutation pathogenicity and WMH severity.

Main Methods:

  • Brain MRI was used to identify lacunar infarctions and WMH in a proband.
  • Next-generation sequencing was performed on the proband and family members to identify CSVD-related genes.
  • Literature review of AD-HTRA1 cases was conducted, and Combined Annotation Dependent Depletion (CADD) scores were analyzed to assess mutation pathogenicity and its relationship with WMH.

Main Results:

  • A heterozygous missense mutation c.854C>T (p.P285L) in the HTRA1 gene was identified in the proband and family members.
  • Retrospective analysis of 5 families with this mutation revealed early onset, frequent cognitive impairment, and potential co-occurrence of alopecia and spondylosis.
  • A significant association was found between WMH severity and the mutated CADD score (p<0.05).

Conclusions:

  • The clinical presentation of AD-HTRA1 with the c.854C>T (p.P285L) HTRA1 mutation resembles CARASIL, characterized by moderate to severe WMH and lacunar infarction on brain MRI.
  • The severity of WMH is influenced by the specific mutation site within the HTRA1 gene.
  • Mutation pathogenicity scores can effectively predict the severity of WMH in patients with AD-HTRA1.
Abstract

Keywords:
Autosomal dominant hereditaryCerebral small vessel diseaseHTRA1Heterozygous mutation

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