Frontiers in Endocrinology · 12 authors, 3 centres
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This study reports six patients with diabetes from three families carrying WFS1 variants, including three novel mutations. A rare manifestation of dilated cardiomyopathy was identified in one patient, and brain atrophy was detected on MRI at age 7 years and 3 months, the earliest reported. RNA sequencing revealed differentially expressed genes enriched in immune-related pathways and abnormal splicing of HLA-DRB1, suggesting a potential modifier role in diabetes pathogenesis.
**Background:** WFS1-related disorders encompass a spectrum of clinical phenotypes, including diabetes mellitus, optic atrophy, deafness, and neurodegeneration, with both autosomal recessive and dominant inheritance patterns. The clinical heterogeneity and incomplete penetrance pose challenges for diagnosis and genetic counseling. This study aimed to characterize the clinical and genetic features of patients with WFS1 variants and explore transcriptomic differences via RNA sequencing.
**Methods:** Three probands and one elder brother from three families were systematically evaluated for endocrine, metabolic, neurologic, cardiovascular, ophthalmologic, and hearing abnormalities. Whole-exome sequencing was performed on the probands, and RNA sequencing was conducted on four patients, their parents carrying WFS1 variants, and four gender- and age-matched children with type 1 diabetes mellitus (T1DM). Differential gene expression analysis and splicing analysis were performed.
**Key Results:** Six patients had diabetes. Patient 5 presented with dilated cardiomyopathy at age 7 years and 3 months, a rare manifestation of WFS1-related disease, and brain atrophy was detected on MRI at the same age—the earliest reported. Five pathogenic or likely pathogenic WFS1 variants were identified: c.1348dupC (p.His450Profs*93), c.1381A>C (p.Thr461Pro), c.1329C>G (p.Ser443Arg), c.2081delA (p.Glu694Glyfs*16), and c.1350-1356delinsGCA (p.His450Glnfs*26). Three of these (c.1348dupC, c.2081delA, c.1350-1356delinsGCA) were novel. RNA sequencing identified 80 differentially expressed genes between patients and parents (47 down-regulated, 33 up-regulated), enriched in immune-related biological processes such as antigen binding. No significant difference in WFS1 expression was observed. Splicing analysis revealed that exon 1 of HLA-DRB1 was not transcribed in two patients from family 1, while transcription was normal in their parents. The expression level of HLA-DRB1 was lower in patients than in the parent group but higher than in the T1DM group, though the range in normal peripheral blood is wide.
**Clinical Implications:** The study highlights the marked clinical and genetic heterogeneity of WFS1-related disorders, even within the same family. The presence of dilated cardiomyopathy in a young child underscores the need for cardiac surveillance, including regular electrocardiograms and echocardiography. The early detection of brain atrophy at age 7 years suggests that brain MRI should be considered at initial diagnosis of WFS1-related disease. The transcriptomic data suggest that WFS1 variants may influence immune-related pathways, and the abnormal splicing of HLA-DRB1 could be a modifier of diabetes susceptibility. However, due to the small sample size, further studies are needed to confirm these findings and elucidate the mechanisms.