Unveiling Secondary Mutations in Blended Phenotypes: Dual ERCC4 and OTOA Pathogenic Variants Through WES Analysis

This study describes two siblings from consanguineous parents who exhibit intellectual disability, microcephaly, photosensitivity, bilateral sensorineural hearing loss, numerous freckles, and other clinical features that suggest a potential disruption of the nucleotide excision repair (NER) pathway....

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Bibliographic Details
Published in:International journal of molecular sciences 2024-12, Vol.25 (24), p.13471
Main Authors: Failla, Pinella, Saccuzzo, Lucia, Galesi, Ornella, Greco, Donatella, Barresi, Vincenza, Amata, Silvestra, Romano, Corrado, Fichera, Marco
Format: Article
Language:English
Subjects:
Asthma
Child
Consanguinity
Convulsions & seizures
DNA-Binding Proteins - genetics
Exome Sequencing
Female
Genes
Genetic counseling
Genetic testing
Genomes
Genomics
Genotype & phenotype
Gestational age
Hearing loss
Hearing Loss, Sensorineural - genetics
Homozygote
Humans
Intellectual disabilities
Intellectual Disability - genetics
Learning disabilities
Male
Medical genetics
Microcephaly
Mutation
Mutation, Missense
Parents & parenting
Patients
Pedigree
Phenotype
Siblings
Software utilities
Citations: Items that this one cites
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Summary:This study describes two siblings from consanguineous parents who exhibit intellectual disability, microcephaly, photosensitivity, bilateral sensorineural hearing loss, numerous freckles, and other clinical features that suggest a potential disruption of the nucleotide excision repair (NER) pathway. Whole exome sequencing (WES) identified a novel homozygous missense variant in the gene, which was predicted to be pathogenic. However, a subsequent peculiar audiometric finding prompted further investigation, revealing a homozygous deletion in the gene linked to neurosensorial hearing loss. Both variants were located within a run of homozygosity (ROH) on chromosome 16p13.12-p12.2, implicating a complex genetic basis for the observed phenotype. While this study reports a potentially novel variant, it underscores the importance of comprehensive analysis and deep phenotyping in WES data to improve diagnostic accuracy. Our findings advocate for an expanded approach in WES analysis, ensuring more precise diagnoses and improved genetic counseling, particularly when specialized tests for structural variant analysis are unavailable.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms252413471