Gap Junction Beta-2 p.Val84Met Can Cause Autosomal Dominant Syndromic Hearing Loss With Keratoderma.

In this study, we report a case of bilateral mild hearing loss and keratoderma caused by a gap junction beta-2 (GJB2) variant. The proband was a nine-year-old Japanese boy with bilateral mild hearing loss at birth. The proband's father, sister, paternal aunt, and cousins had mild sensorineural hearing loss. Further evaluation revealed keratoderma on the feet of the proband, father, sister, paternal aunt, and cousins. We identified a heterozygous c.250G>A (p.Val84Met) variant in GJB2 as the cause of the autosomal dominant syndromic hearing loss with the skin disorder in this Japanese family and delineated the pathological significance of the variant. The Val84Met variant in GJB2 contributes to the autosomal dominant form of syndromic hearing loss with keratoderma.

Novel Digenic Variants in COL4A4 and COL4A5 Causing X-Linked Alport Syndrome: A Case Report.

Introduction: Alport syndrome (AS) is a hereditary, progressive kidney disease characterized by structural abnormalities and dysfunction of the glomerular basement membrane (GBM). AS is classified as X-linked, autosomal, and digenic. The number of cases of digenic AS has increased, but the genotype-phenotype correlation of patient with digenic AS is still unclear. Here, we present a case of digenic AS with novel digenic missense variants in COL4A4 (c.827G>C, p.Gly276Ala) and COL4A5 (c.4369G>C, p.Gly1457Arg). Case Presentation: The patient was a 29-year-old Japanese man suffering from persistent microscopic hematuria and proteinuria without kidney function impairment. Kidney biopsy showed focal interstitial foam cell infiltration, global and segmental glomerulosclerosis. Immunofluorescence staining for collagen IV α5 was almost negative in the GBM and Bowman's capsule. Electron microscopy revealed irregular thickening with lamellation and segmental thinning of the GBM. Clinical and pathological findings were consistent with AS. Comprehensive next-generation sequencing revealed a heterozygous missense variant in COL4A4 (c.827G>C, p.Gly276Ala) in exon 1 and a hemizygous missense variant in COL4A5 (c.4369G>C, p.Gly1457Arg) in exon 49 on the patient's paternal and maternal alleles, respectively. The same digenic variants were detected in his sister, and she also showed a similar phenotype. After treatment with angiotensin-converting enzyme inhibitors, proteinuria decreased from 2.3 to 1.1 g/g creatinine, but occult blood persisted. During follow-up, kidney function has been preserved. Conclusion: The novel genotype of our case provides more information on the genotype-phenotype correlation of digenic XLAS, although long-term follow-up is required. The findings in the present case also indicate the importance of genetic tests for family members of a patient diagnosed with digenic AS.

Oculofaciocardiodental syndrome caused by a novel BCOR variant.

Oculofaciocardiodental syndrome is caused by variants in the BCL6 corepressor (BCOR) gene. We identified a novel heterozygous frameshift variant, NM_001123385.2(BCOR):c.2326del, that arose de novo in a Japanese girl with characteristic facial features, congenital heart disease, bilateral syndactyly of toes 2 and 3, congenital cataracts, dental abnormalities, and mild intellectual disability. Reports of BCOR variants are rare, and further case accumulation is warranted.