Universität zu Köln

Lal, Dennis, Neubauer, Bernd A., Toliat, Mohammad R., Altmueller, Janine, Thiele, Holger, Nuernberg, Peter, Kamrath, Clemens, Schaenzer, Anne, Sander, Thomas, Hahn, Andreas and Nothnagel, Michael ORCID: 0000-0001-8305-7114 (2016). Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing. PLoS One, 11 (1). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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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 etiologically different diseases. We assess the increase in chance co-occurrence of rare diseases due to consanguinity, i.e. under circumstances that generally favor linkage mapping of recessive disease, and show that this probability can increase by several orders of magnitudes. We conclude that such potential co-occurrence represents an underestimated risk when analyzing rare or undefined diseases in consanguineous families and should be given more consideration in the clinical and genetic evaluation.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Neubauer, Bernd A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Toliat, Mohammad R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Kamrath, Clemens UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaenzer, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Sander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hahn, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Nothnagel, Michael UNSPECIFIED orcid.org/0000-0001-8305-7114 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-287109
DOI:	10.1371/journal.pone.0146040
Journal or Publication Title:	PLoS One
Volume:	11
Number:	1
Date:	2016
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SELENOPROTEIN-N GENE; HYPOPHOSPHATEMIC RICKETS; CYSTIC-FIBROSIS; MUSCULAR-DYSTROPHY; LINKAGE ANALYSIS; MUTATIONS; MYOPATHIES; DISORDERS; SEPN1; HYPERCALCIURIA Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28710