Pilz Robin A, Begemann Matthias, Pfister Surema, Boonsawat Paranchai, Rauch Anita, Kurth Ingo, Felbor Ute, Rath Matthias
Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
Center for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Neurogenetics. 2025 Aug 28;26(1):65. doi: 10.1007/s10048-025-00847-2.
The detection of complex structural variants in patients with familial cerebral cavernous malformations (FCCM) remains challenging. Short-read whole genome sequencing was performed for a patient with strong clinical evidence of FCCM but negative results from previous genetic tests. The analysis revealed a large insertion of an intronic KRIT1 fragment into a coding exon of KRIT1. This novel structural variant results in a frameshift and was classified as pathogenic. Predictive testing can now be offered to asymptomatic family members. This case expands the known mutation spectrum in FCCM and suggests that, after negative whole exome or gene panel sequencing, whole genome sequencing should be offered as a second-line diagnostic test.
在患有家族性脑海绵状畸形（FCCM）的患者中检测复杂结构变异仍然具有挑战性。对一名有强烈FCCM临床证据但先前基因检测结果为阴性的患者进行了短读长全基因组测序。分析发现一个内含子KRIT1片段大量插入到KRIT1的一个编码外显子中。这种新的结构变异导致移码，并被分类为致病性变异。现在可以为无症状的家庭成员提供预测性检测。该病例扩展了FCCM中已知的突变谱，并表明在全外显子组或基因panel测序结果为阴性后，应将全基因组测序作为二线诊断检测方法。
