Yaramis Ahmet, Lochmüller Hanns, Töpf Ana, Sonmezler Ece, Yilmaz Elmasnur, Hiz Semra, Yis Uluc, Gungor Serdal, Ipek Polat Ayse, Edem Pinar, Beltran Sergi, Laurie Steven, Yaramis Aysenur, Horvath Rita, Oktay Yavuz
Pediatric Neurology Clinic (A.Y.), Private Office, Diyarbakir, Turkey; Children's Hospital of Eastern Ontario Research Institute (H.L.), University of Ottawa, Canada; Division of Neurology (H.L.), Department of Medicine, The Ottawa Hospital, Canada; John Walton Muscular Dystrophy Research Centre (A.T.), Institute of Genetic Medicine, Newcastle University, UK; Dokuz Eylul University (S.H., E.S., E.Y., Y.O.), Izmir International Biomedicine and Genome Institute, Turkey; Faculty of Medicine (S.H., U.Y., A.I.P., P.E.), Department of Paediatric Neurology, Dokuz Eylul University, Izmir, Turkey; Faculty of Medicine (S.G.), Turgut Ozal Research Center, Department of Paediatric Neurology, Inonu University, Malatya, Turkey; CNAG-CRG (S.L., H.L., S.B.), Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Spain; Universitat Pompeu Fabra (S.L.), Barcelona, Spain; Koc University (A.Y.), School of Medicine, Medical Student, Istanbul, Turkey; Department of Clinical Neurosciences (R.H.), University of Cambridge School of Clinical Medicine, UK; Izmir Biomedicine and Genome Center (Y.O.), Dokuz Eylul University Health Campus, Turkey; and Faculty of Medicine (Y.O.), Department of Medical Biology, Dokuz Eylul University, Izmir, Turkey.
Neurol Genet. 2020 Jan 10;6(1):e392. doi: 10.1212/NXG.0000000000000392. eCollection 2020 Feb.
This study presents the neurologic phenotypes of 2 brothers with a novel homozygous mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases.
Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents.
We have identified a homozygous missense mutation in (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease.
has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that -related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established.
本研究呈现了2名兄弟的神经学表型，他们携带一种新的纯合突变，该突变是在一个大型的土耳其神经遗传病近亲队列中鉴定出来的。
使用RD-Connect基因组-表型分析平台，对有早发性神经遗传病患儿的近亲家庭进行全外显子测序和生物信息学分析。我们还对未受影响的兄弟姐妹和父母进行了临床、脑电图和神经影像学分析。
我们在2名患有伴脑室周围白质脑病和眼部缺陷的小血管性脑疾病的兄弟姐妹中，鉴定出（p.Gly1278Ser，NM_001845.5:c.3832G>T）的纯合错义突变。呈现的症状包括轻度无力、偏瘫步态、锥体束征和癫痫发作，而他们的智力和行为功能正常。父母和5名兄弟姐妹（3名男孩和2名女孩）均为该变异的杂合子。他们未表现出小血管疾病的任何临床或实验室体征。
此前已与大脑和其他器官的显性小血管疾病相关，在杂合突变携带者中具有高外显率。我们的研究结果提供了证据，表明相关脑病可呈常染色体隐性遗传方式，这对咨询、预后和治疗很重要。基因型-表型相关性仍有待确定。
