Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing.
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 illust...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4720433?pdf=render |
| _version_ | 1818302075343208448 |
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| author | Dennis Lal Bernd A Neubauer Mohammad R Toliat Janine Altmüller Holger Thiele Peter Nürnberg Clemens Kamrath Anne Schänzer Thomas Sander Andreas Hahn Michael Nothnagel |
| author_facet | Dennis Lal Bernd A Neubauer Mohammad R Toliat Janine Altmüller Holger Thiele Peter Nürnberg Clemens Kamrath Anne Schänzer Thomas Sander Andreas Hahn Michael Nothnagel |
| author_sort | Dennis Lal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T05:33:08Z |
| format | Article |
| id | doaj.art-ee7b5173aa644cdfb931e8c62b83260f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T05:33:08Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-ee7b5173aa644cdfb931e8c62b83260f2022-12-21T23:58:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01111e014604010.1371/journal.pone.0146040Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing.Dennis LalBernd A NeubauerMohammad R ToliatJanine AltmüllerHolger ThielePeter NürnbergClemens KamrathAnne SchänzerThomas SanderAndreas HahnMichael NothnagelMassively 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.http://europepmc.org/articles/PMC4720433?pdf=render |
| spellingShingle | Dennis Lal Bernd A Neubauer Mohammad R Toliat Janine Altmüller Holger Thiele Peter Nürnberg Clemens Kamrath Anne Schänzer Thomas Sander Andreas Hahn Michael Nothnagel Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing. PLoS ONE |
| title | Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing. |
| title_full | Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing. |
| title_fullStr | Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing. |
| title_full_unstemmed | Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing. |
| title_short | Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing. |
| title_sort | increased probability of co occurrence of two rare diseases in consanguineous families and resolution of a complex phenotype by next generation sequencing |
| url | http://europepmc.org/articles/PMC4720433?pdf=render |
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