Becklin Centre, Leeds and York Partnership NHS Foundation Trust, Leeds, UK.
Leeds Institute of Medical Research, University of Leeds, Leeds, UK.
Schizophr Bull. 2021 Apr 29;47(3):796-802. doi: 10.1093/schbul/sbaa161.
We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for the affected haplotype in 12 further apparently unaffected members of the family. Psychiatric reports suggested an endophenotype of milder psychiatric illness in 4 of these individuals. Exome and genome sequencing revealed no potentially pathogenic coding or structural variants within the risk haplotype. Filtering for noncoding variants with a minor allele frequency of <0.05 identified 17 variants predicted to have significant effects, the 2 most significant being within or adjacent to the SCEL gene. RNA sequencing of blood from an affected homozygote showed the upregulation of transcription from NDFIP2 and SCEL. NDFIP2 is highly expressed in brain, unlike SCEL, and is involved in determining T helper (Th) cell type 1 and Th2 phenotypes, which have previously been implicated with schizophrenia.
我们报告了一个有亲缘关系的家族，其中精神分裂症符合隐性遗传的罕见、部分外显率易感等位基因的方式分离。从两对半表亲之间的 4 次婚姻中，有 6 个后代被诊断为精神障碍。同系基因图谱显示，所有受影响的个体共享一条位于染色体 13q22.2-31.1 上的 6.1Mb 纯合区域，包含 13 个编码蛋白的基因。微卫星分析证实，该家族中 12 名进一步表现为明显未受影响的成员的受影响单倍型是纯合的。精神科报告表明，其中 4 名个体存在较轻的精神疾病表型。外显子组和基因组测序未发现风险单倍型内潜在的致病性编码或结构变异。对杂合子频率<0.05 的非编码变异进行过滤，鉴定出 17 个具有显著影响的变异，其中 2 个最显著的变异位于 SCEL 基因内或附近。受影响的纯合子血液的 RNA 测序显示转录从 NDFIP2 和 SCEL 上调。NDFIP2 在大脑中高表达，与 SCEL 不同，它参与决定辅助性 T 细胞 (Th) 1 型和 Th2 表型，这两种表型先前与精神分裂症有关。
