title: Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing.
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.
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.|Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, 35392, Giessen, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Lal
authors.affiliation: Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, 35392, Giessen, Germany.
authors.forename: Bernd A
authors.initials: BA
authors.lastname: Neubauer
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Pediatrics, University Medical Faculty Giessen, 35392, Giessen, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kamrath
authors.affiliation: Institute of Neuropathology University Medical Faculty Giessen and Marburg, 35392, Giessen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schänzer
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.affiliation: Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, 35392, Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hahn
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D009224:Myotonia Congenita / Q000150:complications / Q000235:genetics; D035583:Rare Diseases / Q000235:genetics; D063730:Rickets, Hypophosphatemic / Q000150:complications / Q000235:genetics; D051140:Selenoproteins / Q000235:genetics*; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; C435489:SELENON protein, human; C493562:SLC34A3 protein, human; D051140:Selenoproteins; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc