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PubMed · 8539657

[Blood relationship].

Abstract

In every-day medical practice, blood relationship of spouses hardly ever play an important part. Mainly for genetic counselors and pediatricians the question of consanguinity of a child's parents arises when either a rare, often hereditary, disorder is diagnosed for the first time in a family, or potential parents want information on the risk for hereditary diseases. A probability calculus based on the corresponding hereditary factors of the joint ancestors establishes how likely homozygotes for hereditary diseases among the offspring of [blood]-related spouses - often cousins of the first or second degree - is. Furthermore, proof of the parents' consanguinity may explain a child's unexpected hereditary disease [especially autosomal recessive disorders] and, at the same time, it means a higher risk of repetition for the affected child's desired siblings. Incest represents a special form of genetic risk; this question arises either in connection with the adoption of a child, which was conceived by an incestuous couple, or with such a child's own family planning later on. Even the parents' descent from an ethnically, politically, religiously or linguistically isolated background may gave a similar impact on the appearance of hereditary disorders: an accumulation of rare genes has to be taken into account; factors causing disorders have to be expected among these genes, too. In the following, all major aspects of the situations described above will be given in detail.

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BibTeXRIS

U Theile, S Hoffmann. 1995. [Blood relationship].. https://pubmed.ncbi.nlm.nih.gov/8539657/

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Whole-Exome Sequencing in a Consanguinity-Enriched South Indian Retinitis Pigmentosa Cohort: Diagnostic Yield and Molecular Spectrum.

PURPOSE: To determine the molecular diagnostic yield, variant spectrum, inheritance architecture, and influence of consanguinity on whole-exome sequencing outcomes in a South Indian retinitis pigmentosa (RP) cohort. DESIGN: Prospective, registry-based cohort study. SUBJECTS: A total of 113 affected participants were enrolled through the Aravind Registry for Inherited Diseases of the Eye, including 109 unrelated probands and 4 affected relatives from already represented families. Primary analyses were restricted to the 109 unrelated probands. METHODS: Whole-exome sequencing was performed using a clinical exome workflow. Variants were interpreted using American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and cases were categorized as solved, possibly solved, inconclusive, or unsolved using prespecified inheritance-aware rules. MAIN OUTCOME MEASURES: Molecular diagnostic yield, distribution of implicated genes and variant classes, inheritance architecture, and diagnostic yield stratified by consanguinity status. RESULTS: Among the 109 unrelated probands, mean age at testing was 39.3 ± 14.1 years and 58.7% were male. Whole-exome sequencing identified 186 distinct rare variants across 92 inherited retinal disease genes, including 26 pathogenic and 33 likely pathogenic variants. A molecular diagnosis was established in 50 of 109 probands (45.9%), including 42 solved and 8 possibly solved cases; 45 (41.3%) were inconclusive and 14 (12.8%) remained unsolved, including 4 (3.7%) in whom no candidate variant was identified. EYS, USH2A, and ADGRV1 were the most frequently implicated genes. Autosomal recessive (AR) disease predominated (44/50, 88.0%). Consanguineous AR cases were exclusively homozygous (17/17); notably, 68.0% of nonconsanguineous AR cases were also homozygous (P = 0.013). Diagnostic yield was higher in consanguineous probands (51.4% vs. 41.7%), without reaching significance. Recurrent alleles included an established South Asian founder variant (MFSD8 c.1361T>C) and candidate founder alleles in EYS (c.4321C>T) and ADGRV1 (c.14329C>T). CONCLUSIONS: Whole-exome sequencing established a molecular diagnosis in nearly half of this South Indian RP cohort and revealed a predominantly recessive, homozygosity-enriched architecture shaped by consanguinity. These findings define a region-specific variant landscape to support clinical interpretation, genetic counseling, and future trial enrollment in this underrepresented population. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.

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