Department of Neurology, Neuromuscular Diseases Research Laboratory, Hacettepe University, Medical Faculty, Sihhiye Ankara 06100, Turkey.
Department of Medical Genetics, Hacettepe University, Medical Faculty, Ankara, Turkey.
J Stroke Cerebrovasc Dis. 2021 Sep;30(9):105997. doi: 10.1016/j.jstrokecerebrovasdis.2021.105997. Epub 2021 Jul 21.
To identify the underlying genetic defect for a consanguineous family with an unusually high number of members affected by cerebral small vessel disease.
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.
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.
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.
鉴定一个有血缘关系的家族中存在的导致大脑小血管疾病的遗传缺陷，该家族中受影响的成员数量异常多。
对该家族的 6 名成员（其中 3 名病情严重）进行临床和影像学评估。对多个成员进行 SNP 基因分型，以显示全基因组的纯合性。通过 Sanger 测序对最有可能的候选基因 HTRA1 的编码变异进行探索。广泛回顾已发表的 HTRA1 相关表型，以探讨受影响等位基因数量对表型表达的影响。
全基因组纯合性作图确定了位于 10q26.3 染色体上的一个 3.2 Mbp 长的区域，HTRA1 基因位于该区域。HTRA1 测序揭示了一个进化上保守的新纯合 c.824C>T（p.Pro275Leu）突变，影响 HtrA1 的丝氨酸蛋白酶结构域。纯合子的认知和运动功能恶化起病早，与 CARASIL 一致。然而，纯合子之间存在明显的表型变异性，包括脱发，这是 CARASIL 的一个标志性特征。所有杂合子均表现为 CADASIL 2 型，尽管没有严重的临床表现，但存在脊柱间盘退变和多种神经影像学发现，包括脑白质病变和微出血。
通过对一个家族中分离的最大数量的纯合子和杂合子进行评估，我们清楚地表明，CARASIL 和 CADASIL 2 是同一疾病的两种临床表现，严重程度不同。鉴于 HTRA1 相关表型的半显性遗传，无论有无症状，都必须为 HTRA1 突变的家族所有成员提供基因检测和临床随访。
