Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1

PURPOSE: To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series. METHODS: Seven members of a Dutch family underwent ophthalmological, otological, and genetical examinations in one institution. Fasting serum glucose was assessed in the affected family members. RESULTS: All affected individuals showed loss of neuroretinal rim of the optic nerve at fundoscopy with enlarged blind spots at perimetry. They showed a red-green color vision defect at color vision tests and deviations at visually evoked response tests. The audiograms of the affected individuals showed hearing loss and were relatively flat. The unaffected individuals showed no visual deviations or hearing impairment. The affected family members had no glucose intolerance. Leber hereditary optic neuropathy (LHON) mitochondrial mutations and mutations in the Optic atrophy-1 gene (OPA1) were excluded. In the affected individuals, a novel missense mutation c.2508G>C (p.Lys836Asn) in exon 8 of WFS1 was identified. CONCLUSIONS: This study describes the phenotype of a family with autosomal dominant optic neuropathy and hearing impairment associated with a novel missense mutation in WFS1

Is routine karyotyping required in prenatal samples with a molecular or metabolic referral?

As a routine, karyotyping of invasive prenatal samples is performed as an adjunct to referrals for DNA mutation detection and metabolic testing. We performed a retrospective study on 500 samples to assess the diagnostic value of this procedure. These samples included 454 (90.8%) chorionic villus (CV) and 46 (9.2%) amniocenteses specimens. For CV samples karyotyping was based on analyses of both short-term culture (STC) and long-term culture (LTC) cells. Overall, 19 (3.8%) abnormal karyotypes were denoted: four with a common aneuploidy (trisomy 21, 18 and 13), two with a sex chromosomal aneuploidy (Klinefelter syndrome), one with a sex chromosome mosaicism and twelve with various autosome mosaicisms. In four cases a second invasive test was performed because of an abnormal finding in the STC. Taken together, we conclude that STC and LTC karyotyping has resulted in a diagnostic yield of 19 (3.8%) abnormal cases, including 12 cases (2.4%) with an uncertain significance. From a diagnostic point of view, it is desirable to limit uncertain test results as secondary test findings. Therefore, we recommend a more targeted assay, such as e.g. QF-PCR, as a replacement of the STC and to provide parents the autonomy to choose between karyotyping and QF-PCR