Identification of a Novel Deletion Mutation (c.1780delG) and a Novel Splice-Site Mutation (c.1412-1G>A) in the CCM1/KRIT1 Gene Associated with Familial Cerebral Cavernous Malformation in the Chinese Population

Abstract

Cerebral cavernous malformation (CCM) is a congenital vascular anomaly predominantly located within the central nervous system. Its familial forms (familial cerebral cavernous malformation (FCCM)), inherited in an autosomal dominant manner with incomplete penetrance, are attributed to mutations in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes. To date, little is known about the genetic alterations leading to FCCM in the Chinese population. We aimed to investigate the genetic defect of FCCM by DNA sequencing in Chinese families. This study enrolled five Chinese families with FCCM. All index cases underwent surgical treatment and were diagnosed with CCM by pathology; their relatives were diagnosed based on radiological and/or pathological evidence. Genomic DNA was extracted from peripheral blood and amplified using polymerase chain reaction (PCR) for DNA sequencing. The five families comprised a total of 21 affected individuals: 12 of these were symptomatic, and 9 were asymptomatic. Sequence analyses in the index patients disclosed three heterozygous loss-of-function mutations in the CCM1/KRIT1 gene in three families, respectively: a novel deletion mutation (c.1780delG; p.Ala594HisfsX67) in exon 16, a novel splice-site mutation (c.1412-1G>A) in the splice acceptor site in intron 13, and a previously described 4-bp deletion (c.1197_1200delCAAA; p.Gln401ThrfsX10) in exon 12. All of these mutations are predicted to cause a premature termination codon to generate a truncated Krev interaction trapped 1 (Krit1) protein. These mutations segregated in affected relatives. Our findings provided new CCM1 gene mutation profiles, which help to elucidate the pathogenesis of FCCM and will be of great significance in genetic counseling.

Molecular genetic features and clinical manifestations in Chinese familial cerebral cavernous malformation: from a novel KRIT1/CCM1 mutation (c.1119dupT) to an overall view

“…A retrieved result from Web of Science, PubMed, and Wanfang Data Knowledge Service Platform databases since 2000, with the terms familial cerebral cavernous malformations, mutation, and Chinese, articles published in English or Chinese with essential information about the mutations were included. We collected 24 pathogenetic alterations of fCCMs first identified in the Chinese population ( Chen et al, 2002 ; Xu et al, 2003 ; Mao et al, 2005 , 2016 ; Ji et al, 2006 ; Zhao et al, 2011 ; Wang et al, 2013 , 2017 , 2018 ; Zhu et al, 2014 ; Yang et al, 2017 ; Du et al, 2019 ; Han et al, 2020 ; Jiang et al, 2020 ; Yang L. et al, 2020 ; Yang Q. et al, 2020 ; Zhang et al, 2020 ; Liu et al, 2022 ). As exhibited in Table 3 , the majority (18/24) of Chinese fCCMs pathogenetic alterations are in KRIT1/CCM1 gene.…”

“…The incidence of fCCMs accounts for about 10−15% of all CCM cases ( Zhao et al, 2011 ), and its incidence rate displays obvious geographical characteristics, with fCCMs incidence rates as high as 50% in Hispanic Americans and 10−40% in Caucasian populations ( Rigamonti et al, 1988 ; Labauge et al, 2007 ). Epidemiologically, the incidence of fCCMs in Han Chinese has not been reported, systematic studies on Han Chinese fCCMs families are extremely rare, and clinically definite diagnosis of Han Chinese fCCMs is also rare ( Yang et al, 2017 ; Liu et al, 2022 ). However, some Chinese-specific CCMs gene mutation loci have been found sporadically ( Chen et al, 2002 ; Yang et al, 2017 , 2018 ; Jih et al, 2018 ; Yang L. et al, 2020 ).…”

“…Epidemiologically, the incidence of fCCMs in Han Chinese has not been reported, systematic studies on Han Chinese fCCMs families are extremely rare, and clinically definite diagnosis of Han Chinese fCCMs is also rare ( Yang et al, 2017 ; Liu et al, 2022 ). However, some Chinese-specific CCMs gene mutation loci have been found sporadically ( Chen et al, 2002 ; Yang et al, 2017 , 2018 ; Jih et al, 2018 ; Yang L. et al, 2020 ). Therefore, it is meaningful to uncover the genetic phenotype of Han Chinese fCCMs by continuously enriching the fCCMs’ genomic alteration spectrum in the Chinese population.…”

CCM1 and CCM2 variants in patients with cerebral cavernous malformation in an ethnically Chinese population in Taiwan

“…Among those studies conducted in the ethnic Chinese population, most were case reports. One case series recruited five families and reported three novel variants causing early truncation 15 . Only two studies performed molecular screening of patients with CCMs from their brain MRI data 8,9 .…”

Identification of novel missense mutations (c.1156T>C and c.785T>C) in the PSEN1 gene in Chinese families with early-onset Alzheimer’s disease

“…To date, little is known about the genetic alterations that lead to early-onset Alzheimer's disease in the Chinese population [5]. Some researchers have found that pathogenic mutations of autosomal dominant diseases usually exhibit remarkable genetic heterogeneity among different races and ethnicities [8,9]. In the current study, we investigated the genetic defects of early-onset Alzheimer's disease in two Chinese families.…”