Christian Medical College Vellore, India.
Moulana Hospital, Mallapuram, India.
J Clin Endocrinol Metab. 2022 Apr 19;107(5):1328-1336. doi: 10.1210/clinem/dgac002.
Wolfram syndrome (WFS) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes, diabetes insipidus, optic atrophy, deafness, and progressive neurodegeneration. However, due to the progressive nature of the disease and a lack of complete clinical manifestations, a confirmed diagnosis of WFS at the time of onset of diabetes is a challenge.
With WFS1 rare heterozygous variants reported in diabetes, there is a need for comprehensive genetic screening strategies for the early diagnosis of WFS and delineating the phenotypic spectrum associated with the WFS1 gene variants in young-onset diabetes.
This case series of 11 patients who were positive for WFS1 variants were identified with next-generation sequencing (NGS)-based screening of 17 genemonogenic diabetes panel. These results were further confirmed with Sanger sequencing.
9 out of 11 patients were homozygous for pathogenic/likely pathogenic variants in the WFS1 gene. Interestingly, 3 of these probands were positive for the novel WFS1 (NM_006005.3): c.1107_1108insA (p.Ala370Serfs*173) variant, and haplotype analysis suggested a founder effect in 3 families from Southern India. Additionally, we identified 2 patients with young-onset diabetes who were heterozygous for a likely pathogenic variant or a variant of uncertain significance in the WFS1 gene.
These results project the need for NGS-based parallel multigene testing as a tool for early diagnosis of WFS and identify heterozygous WFS1 variants implicated in young-onset diabetes.
Wolfram 综合征（WFS）是一种罕见的常染色体隐性遗传病，其特征为青少年发病型糖尿病、尿崩症、视神经萎缩、耳聋和进行性神经退行性变。然而，由于疾病的进行性特征和不完全的临床表现，在糖尿病发病时确诊 WFS 具有挑战性。
由于在糖尿病中已报道 WFS1 罕见杂合变异体，因此需要全面的遗传筛选策略，以便对 WFS 进行早期诊断，并阐明与 WFS1 基因变异相关的青少年发病型糖尿病的表型谱。
通过基于下一代测序（NGS）的 17 个基因的糖尿病 panel 对 11 例 WFS1 变异阳性的患者进行了病例系列研究。这些结果通过 Sanger 测序进一步证实。
11 例患者中有 9 例为 WFS1 基因的纯合致病性/可能致病性变异体。有趣的是，这 3 名先证者均为新型 WFS1（NM_006005.3）：c.1107_1108insA（p.Ala370Serfs*173）变异体阳性，并且单体型分析表明在来自印度南部的 3 个家族中存在着一个遗传起源。此外，我们还发现了 2 例患有青少年发病型糖尿病的患者，他们在 WFS1 基因中为杂合可能致病性变异体或意义不明的变异体。
这些结果表明，需要使用基于 NGS 的平行多基因检测作为早期诊断 WFS 的工具，并鉴定出与青少年发病型糖尿病相关的 WFS1 杂合变异体。
