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Whole-Exome Sequencing Identifies Novel Compound Heterozygous ZNF469 Mutations in Two Siblings with Mild Brittle Cornea Syndrome.

ABSTRACT: Connective tissue diseases, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), exhibit a high degree of clinical and genetic heterogeneity. We report two sisters with blue sclerae, joint hypermobility and hearing loss. Whole-exome sequencing identified two compound heterozygous ZNF469 loss-of-function mutations due to a frameshift. Since these findings indicate the presence of brittle cornea syndrome (BCS), we performed ocular optical coherence tomography (OCT) and pachymetry, which revealed a moderate decrease in corneal thickness. While only one traumatic fracture was observed in each of the patients, a detailed skeletal assessment indicated no specific patterns of bone mass and microstructure reduction as well as normal bone turnover markers. Taken together, our findings point to a mild form of brittle cornea syndrome with a phenotype compatible with the extraskeletal features of OI but also with EDS.

SUBMITTER: Rolvien T

PROVIDER: S-EPMC7415034 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Whole-Exome Sequencing Identifies Novel Compound Heterozygous ZNF469 Mutations in Two Siblings with Mild Brittle Cornea Syndrome.

Rolvien Tim T Kornak Uwe U Linke Stephan J SJ Amling Michael M Oheim Ralf R

Calcified tissue international 20200715 3

Connective tissue diseases, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), exhibit a high degree of clinical and genetic heterogeneity. We report two sisters with blue sclerae, joint hypermobility and hearing loss. Whole-exome sequencing identified two compound heterozygous ZNF469 loss-of-function mutations due to a frameshift. Since these findings indicate the presence of brittle cornea syndrome (BCS), we performed ocular optical coherence tomography (OCT) and pachymet ...[more]

PMID: 32671420

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Project description:PURPOSE: Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. METHODS: We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. RESULTS: Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. CONCLUSIONS: Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis.

Dataset Information

Whole-Exome Sequencing Identifies Novel Compound Heterozygous ZNF469 Mutations in Two Siblings with Mild Brittle Cornea Syndrome.

Publications

Whole-Exome Sequencing Identifies Novel Compound Heterozygous ZNF469 Mutations in Two Siblings with Mild Brittle Cornea Syndrome.

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