Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia.
We present the genetic analyses conducted on a three-generation family (14 individuals) with three members affected with isolated-Hirschsprung disease (HSCR) and one with HSCR and heterochromia iridum (syndromic-HSCR), a phenotype reminiscent of Waardenburg-Shah syndrome (WS4). WS4 is characterized...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3694150?pdf=render |
| _version_ | 1818141184357302272 |
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| author | Long Cui Emily Hoi-Man Wong Guo Cheng Manoel Firmato de Almeida Man-Ting So Pak-Chung Sham Stacey S Cherny Paul Kwong-Hang Tam Maria-Mercè Garcia-Barceló |
| author_facet | Long Cui Emily Hoi-Man Wong Guo Cheng Manoel Firmato de Almeida Man-Ting So Pak-Chung Sham Stacey S Cherny Paul Kwong-Hang Tam Maria-Mercè Garcia-Barceló |
| author_sort | Long Cui |
| collection | DOAJ |
| description | We present the genetic analyses conducted on a three-generation family (14 individuals) with three members affected with isolated-Hirschsprung disease (HSCR) and one with HSCR and heterochromia iridum (syndromic-HSCR), a phenotype reminiscent of Waardenburg-Shah syndrome (WS4). WS4 is characterized by pigmentary abnormalities of the skin, eyes and/or hair, sensorineural deafness and HSCR. None of the members had sensorineural deafness. The family was screened for copy number variations (CNVs) using Illumina-HumanOmni2.5-Beadchip and for coding sequence mutations in WS4 genes (EDN3, EDNRB, or SOX10) and in the main HSCR gene (RET). Confocal microscopy and immunoblotting were used to assess the functional impact of the mutations. A heterozygous A/G transition in EDNRB was identified in 4 affected and 3 unaffected individuals. While in EDNRB isoforms 1 and 2 (cellular receptor) the transition results in the abolishment of translation initiation (M1V), in isoform 3 (only in the cytosol) the replacement occurs at Met91 (M91V) and is predicted benign. Another heterozygous transition (c.-248G/A; -predicted to affect translation efficiency-) in the 5'-untranslated region of EDN3 (EDNRB ligand) was detected in all affected individuals but not in healthy carriers of the EDNRB mutation. Also, a de novo CNVs encompassing DACH1 was identified in the patient with heterochromia iridum and HSCR Since the EDNRB and EDN3 variants only coexist in affected individuals, HSCR could be due to the joint effect of mutations in genes of the same pathway. Iris heterochromia could be due to an independent genetic event and would account for the additional phenotype within the family. |
| first_indexed | 2024-12-11T10:55:51Z |
| format | Article |
| id | doaj.art-5312e00781254ec88bdd1f6efda2d30f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T10:55:51Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5312e00781254ec88bdd1f6efda2d30f2022-12-22T01:10:03ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6663110.1371/journal.pone.0066631Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia.Long CuiEmily Hoi-Man WongGuo ChengManoel Firmato de AlmeidaMan-Ting SoPak-Chung ShamStacey S ChernyPaul Kwong-Hang TamMaria-Mercè Garcia-BarcelóWe present the genetic analyses conducted on a three-generation family (14 individuals) with three members affected with isolated-Hirschsprung disease (HSCR) and one with HSCR and heterochromia iridum (syndromic-HSCR), a phenotype reminiscent of Waardenburg-Shah syndrome (WS4). WS4 is characterized by pigmentary abnormalities of the skin, eyes and/or hair, sensorineural deafness and HSCR. None of the members had sensorineural deafness. The family was screened for copy number variations (CNVs) using Illumina-HumanOmni2.5-Beadchip and for coding sequence mutations in WS4 genes (EDN3, EDNRB, or SOX10) and in the main HSCR gene (RET). Confocal microscopy and immunoblotting were used to assess the functional impact of the mutations. A heterozygous A/G transition in EDNRB was identified in 4 affected and 3 unaffected individuals. While in EDNRB isoforms 1 and 2 (cellular receptor) the transition results in the abolishment of translation initiation (M1V), in isoform 3 (only in the cytosol) the replacement occurs at Met91 (M91V) and is predicted benign. Another heterozygous transition (c.-248G/A; -predicted to affect translation efficiency-) in the 5'-untranslated region of EDN3 (EDNRB ligand) was detected in all affected individuals but not in healthy carriers of the EDNRB mutation. Also, a de novo CNVs encompassing DACH1 was identified in the patient with heterochromia iridum and HSCR Since the EDNRB and EDN3 variants only coexist in affected individuals, HSCR could be due to the joint effect of mutations in genes of the same pathway. Iris heterochromia could be due to an independent genetic event and would account for the additional phenotype within the family.http://europepmc.org/articles/PMC3694150?pdf=render |
| spellingShingle | Long Cui Emily Hoi-Man Wong Guo Cheng Manoel Firmato de Almeida Man-Ting So Pak-Chung Sham Stacey S Cherny Paul Kwong-Hang Tam Maria-Mercè Garcia-Barceló Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia. PLoS ONE |
| title | Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia. |
| title_full | Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia. |
| title_fullStr | Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia. |
| title_full_unstemmed | Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia. |
| title_short | Genetic Analyses of a Three Generation Family Segregating Hirschsprung Disease and Iris Heterochromia. |
| title_sort | genetic analyses of a three generation family segregating hirschsprung disease and iris heterochromia |
| url | http://europepmc.org/articles/PMC3694150?pdf=render |
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