Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease.
<h4>Background and aim</h4>Gene defects contribute to the aetiology of intrahepatic cholestasis. We aimed to explore the outcome of whole-exome sequencing (WES) in a cohort of 51 patients with this diagnosis.<h4>Patients and methods</h4>Both paediatric (n = 33) and adult (n =...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0288907&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832540109667303424 |
|---|---|
| author | Magdaléna Neřoldová Elżbieta Ciara Janka Slatinská Soňa Fraňková Petra Lišková Radana Kotalová Janka Globinovská Markéta Šafaříková Lucie Pfeiferová Hana Zůnová Lenka Mrázová Viktor Stránecký Alena Vrbacká Ondřej Fabián Eva Sticová Daniela Skanderová Jan Šperl Marta Kalousová Tomáš Zima Milan Macek Joanna Pawlowska A S Knisely Stanislav Kmoch Milan Jirsa |
| author_facet | Magdaléna Neřoldová Elżbieta Ciara Janka Slatinská Soňa Fraňková Petra Lišková Radana Kotalová Janka Globinovská Markéta Šafaříková Lucie Pfeiferová Hana Zůnová Lenka Mrázová Viktor Stránecký Alena Vrbacká Ondřej Fabián Eva Sticová Daniela Skanderová Jan Šperl Marta Kalousová Tomáš Zima Milan Macek Joanna Pawlowska A S Knisely Stanislav Kmoch Milan Jirsa |
| author_sort | Magdaléna Neřoldová |
| collection | DOAJ |
| description | <h4>Background and aim</h4>Gene defects contribute to the aetiology of intrahepatic cholestasis. We aimed to explore the outcome of whole-exome sequencing (WES) in a cohort of 51 patients with this diagnosis.<h4>Patients and methods</h4>Both paediatric (n = 33) and adult (n = 18) patients with cholestatic liver disease of unknown aetiology were eligible. WES was used for reassessment of 34 patients (23 children) without diagnostic genotypes in ABCB11, ATP8B1, ABCB4 or JAG1 demonstrable by previous Sanger sequencing, and for primary assessment of additional 17 patients (10 children). Nasopharyngeal swab mRNA was analysed to address variant pathogenicity in two families.<h4>Results</h4>WES revealed biallelic variation in 3 ciliopathy genes (PKHD1, TMEM67 and IFT172) in 4 clinically unrelated index subjects (3 children and 1 adult), heterozygosity for a known variant in PPOX in one adult index subject, and homozygosity for an unreported splice-site variation in F11R in one child. Whereas phenotypes of the index patients with mutated PKHD1, TMEM67, and PPOX corresponded with those elsewhere reported, how F11R variation underlies liver disease remains unclear. Two unrelated patients harboured different novel biallelic variants in IFT172, a gene implicated in short-rib thoracic dysplasia 10 and Bardet-Biedl syndrome 20. One patient, a homozygote for IFT172 rs780205001 c.167A>C p.(Lys56Thr) born to first cousins, had liver disease, interpreted on biopsy aged 4y as glycogen storage disease, followed by adult-onset nephronophthisis at 25y. The other, a compound heterozygote for novel frameshift variant IFT172 NM_015662.3 c.2070del p.(Met690Ilefs*11) and 2 syntenic missense variants IFT172 rs776310391 c.157T>A p.(Phe53Ile) and rs746462745 c.164C>G p.(Thr55Ser), had a severe 8mo cholestatic episode in early infancy, with persisting hyperbilirubinemia and fibrosis on imaging studies at 17y. No patient had skeletal malformations.<h4>Conclusion</h4>Our findings suggest association of IFT172 variants with non-syndromic cholestatic liver disease. |
| format | Article |
| id | doaj-art-6323603b02e54de1911ce31cb220105f |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-6323603b02e54de1911ce31cb220105f2025-02-05T05:32:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01187e028890710.1371/journal.pone.0288907Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease.Magdaléna NeřoldováElżbieta CiaraJanka SlatinskáSoňa FraňkováPetra LiškováRadana KotalováJanka GlobinovskáMarkéta ŠafaříkováLucie PfeiferováHana ZůnováLenka MrázováViktor StráneckýAlena VrbackáOndřej FabiánEva SticováDaniela SkanderováJan ŠperlMarta KalousováTomáš ZimaMilan MacekJoanna PawlowskaA S KniselyStanislav KmochMilan Jirsa<h4>Background and aim</h4>Gene defects contribute to the aetiology of intrahepatic cholestasis. We aimed to explore the outcome of whole-exome sequencing (WES) in a cohort of 51 patients with this diagnosis.<h4>Patients and methods</h4>Both paediatric (n = 33) and adult (n = 18) patients with cholestatic liver disease of unknown aetiology were eligible. WES was used for reassessment of 34 patients (23 children) without diagnostic genotypes in ABCB11, ATP8B1, ABCB4 or JAG1 demonstrable by previous Sanger sequencing, and for primary assessment of additional 17 patients (10 children). Nasopharyngeal swab mRNA was analysed to address variant pathogenicity in two families.<h4>Results</h4>WES revealed biallelic variation in 3 ciliopathy genes (PKHD1, TMEM67 and IFT172) in 4 clinically unrelated index subjects (3 children and 1 adult), heterozygosity for a known variant in PPOX in one adult index subject, and homozygosity for an unreported splice-site variation in F11R in one child. Whereas phenotypes of the index patients with mutated PKHD1, TMEM67, and PPOX corresponded with those elsewhere reported, how F11R variation underlies liver disease remains unclear. Two unrelated patients harboured different novel biallelic variants in IFT172, a gene implicated in short-rib thoracic dysplasia 10 and Bardet-Biedl syndrome 20. One patient, a homozygote for IFT172 rs780205001 c.167A>C p.(Lys56Thr) born to first cousins, had liver disease, interpreted on biopsy aged 4y as glycogen storage disease, followed by adult-onset nephronophthisis at 25y. The other, a compound heterozygote for novel frameshift variant IFT172 NM_015662.3 c.2070del p.(Met690Ilefs*11) and 2 syntenic missense variants IFT172 rs776310391 c.157T>A p.(Phe53Ile) and rs746462745 c.164C>G p.(Thr55Ser), had a severe 8mo cholestatic episode in early infancy, with persisting hyperbilirubinemia and fibrosis on imaging studies at 17y. No patient had skeletal malformations.<h4>Conclusion</h4>Our findings suggest association of IFT172 variants with non-syndromic cholestatic liver disease.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0288907&type=printable |
| spellingShingle | Magdaléna Neřoldová Elżbieta Ciara Janka Slatinská Soňa Fraňková Petra Lišková Radana Kotalová Janka Globinovská Markéta Šafaříková Lucie Pfeiferová Hana Zůnová Lenka Mrázová Viktor Stránecký Alena Vrbacká Ondřej Fabián Eva Sticová Daniela Skanderová Jan Šperl Marta Kalousová Tomáš Zima Milan Macek Joanna Pawlowska A S Knisely Stanislav Kmoch Milan Jirsa Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease. PLoS ONE |
| title | Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease. |
| title_full | Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease. |
| title_fullStr | Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease. |
| title_full_unstemmed | Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease. |
| title_short | Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease. |
| title_sort | exome sequencing reveals ift172 variants in patients with non syndromic cholestatic liver disease |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0288907&type=printable |
| work_keys_str_mv | AT magdalenaneroldova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT elzbietaciara exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT jankaslatinska exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT sonafrankova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT petraliskova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT radanakotalova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT jankaglobinovska exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT marketasafarikova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT luciepfeiferova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT hanazunova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT lenkamrazova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT viktorstranecky exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT alenavrbacka exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT ondrejfabian exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT evasticova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT danielaskanderova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT jansperl exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT martakalousova exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT tomaszima exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT milanmacek exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT joannapawlowska exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT asknisely exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT stanislavkmoch exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease AT milanjirsa exomesequencingrevealsift172variantsinpatientswithnonsyndromiccholestaticliverdisease |