Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing

PloS One
Dennis LalMichael Nothnagel

Abstract

Massively parallel sequencing of whole genomes and exomes has facilitated a direct assessment of causative genetic variation, now enabling the identification of genetic factors involved in rare diseases (RD) with Mendelian inheritance patterns on an almost routine basis. Here, we describe the illustrative case of a single consanguineous family where this strategy suffered from the difficulty to distinguish between two etiologically distinct disorders, namely the co-occurrence of hereditary hypophosphatemic rickets (HRR) and congenital myopathies (CM), by their phenotypic manifestation alone. We used parametric linkage analysis, homozygosity mapping and whole exome-sequencing to identify mutations underlying HRR and CM. We also present an approximate approach for assessing the probability of co-occurrence of two unlinked recessive RD in a single family as a function of the degree of consanguinity and the frequency of the disease-causing alleles. Linkage analysis and homozygosity mapping yielded elusive results when assuming a single RD, but whole-exome sequencing helped to identify two mutations in two genes, namely SLC34A3 and SEPN1, that segregated independently in this family and that have previously been linked to two etiolo...Continue Reading

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Citations

Dec 24, 2016·Neuropathology and Applied Neurobiology·M SchuelkeA Oldfors
Oct 4, 2017·Human Molecular Genetics·Adrian Palencia-CamposVictor L Ruiz-Perez
Oct 5, 2019·American Journal of Medical Genetics. Part a·Ozlem Akgun-DoganKoray Boduroğlu
May 10, 2019·Nature Reviews. Nephrology·Dieter HaffnerAgnès Linglart
Feb 2, 2021·Frontiers in Neurology·Celina von StülpnagelUNKNOWN NETRE Consortium
Jan 1, 2022·Molecular Genetics & Genomic Medicine·Limor KalfonTzipora C Falik-Zaccai

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Methods Mentioned

BETA
biopsy
exome sequencing
PCR
biopsies

Software Mentioned

HomozygosityMapper2012
Illumina Realtime Analysis
GenomeStudio
Superlink
CASAVA

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