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Invest Ophthalmol Vis Sci. 2014 Oct 23;55(11):7562-71. doi: 10.1167/iovs.14-14938.

Contribution of mutation load to the intrafamilial genetic heterogeneity in a large cohort of Spanish retinal dystrophies families.

Author information

1
Department of Genetics, Fundacion Jimenez Diaz University Hospital (IIS - FJD, UAM), Madrid, Spain Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
2
Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain Unidad de Genética Molecular, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
3
Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain Grupo de Investigación en Enfermedades Neurosensoriales, Instituto de Investigación Sanitaria IIS-La Fe, Valencia, Spain.
4
Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain Department of Ophthalmology, Fundacion Jimenez Diaz University Hospital (IIS - FJD, UAM), Madrid, Spain.

Abstract

PURPOSE:

The aim of this study was to deepen our knowledge on the basis of intrafamilial genetic heterogeneity of inherited retinal dystrophies (RD) to further discern the contribution of individual alleles to the pathology.

METHODS:

Families with intrafamilial locus and/or allelic heterogeneity were selected from a cohort of 873 characterized of 2468 unrelated RD families. Clinical examination included visual field assessments, electrophysiology, fundus examination, and audiogram. Molecular characterization was performed using a combination of different methods: genotyping microarray, single strand conformational polymorphism (SSCP), denaturing high pressure liquid chromatography (dHPLC), high resolution melt (HRM), multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, whole-genome homozygosity mapping, and next-generation sequencing (NGS).

RESULTS:

Overall, intrafamilial genetic heterogeneity was encountered in a total of 8 pedigrees. There were 5 of 873 families (~0.6%) with causative mutations in more than one gene (locus heterogeneity), involving the genes: (1) USH2A, RDH12, and TULP1; (2) PDE6B and a new candidate gene; (3) CERKL and CRB1; (4) BBS1 and C2orf71; and (5) ABCA4 and CRB1. Typically, in these cases, each mutated gene was associated with different phenotypes. In the 3 other families (~0.35%), different mutations in the same gene (allelic heterogeneity) were found, including the frequent RD genes ABCA4 and CRB1.

CONCLUSIONS:

This systematic research estimates that the frequency of overall mutation load promoting RD intrafamilial heterogeneity in our cohort of Spanish families is almost 1%. The identification of the genetic mechanisms underlying RD locus and allelic heterogeneity is essential to discriminate the real contribution of the monoallelic mutations to the disease, especially in the NGS era. Moreover, it is decisive to provide an accurate genetic counseling and in disease treatment.

KEYWORDS:

intrafamilial heterogeneity; mutation load; retinal dystrophies

PMID:
25342620
DOI:
10.1167/iovs.14-14938
[Indexed for MEDLINE]

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