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Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome
A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. U...
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| Published in: | European journal of human genetics : EJHG 2018-09, Vol.26 (9), p.1266-1271 |
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| container_end_page | 1271 |
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| container_title | European journal of human genetics : EJHG |
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| creator | Brancati, Francesco Camerota, Letizia Colao, Emma Vega-Warner, Virginia Zhao, Xiangzhong Zhang, Ruixiao Bottillo, Irene Castori, Marco Caglioti, Alfredo Sangiuolo, Federica Novelli, Giuseppe Perrotti, Nicola Otto, Edgar A |
| description | A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome. |
| doi_str_mv | 10.1038/s41431-018-0183-6 |
| format | article |
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In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.</description><identifier>ISSN: 1018-4813</identifier><identifier>EISSN: 1476-5438</identifier><identifier>DOI: 10.1038/s41431-018-0183-6</identifier><identifier>PMID: 29891882</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Adult ; Alleles ; Bone dysplasia ; Codon, Nonsense ; Fibrosis ; Heredity ; Heterozygote ; Humans ; Hypopituitarism ; Hypopituitarism - genetics ; Hypopituitarism - pathology ; Lethality ; Liver ; Male ; Membrane Proteins - genetics ; Mutation, Missense ; Nephronophthisis ; Phenotype ; Phenotypes ; Retinitis ; Retinitis pigmentosa ; Retinitis Pigmentosa - genetics ; Retinitis Pigmentosa - pathology ; RNA Splicing ; Skeleton ; Splicing</subject><ispartof>European journal of human genetics : EJHG, 2018-09, Vol.26 (9), p.1266-1271</ispartof><rights>Copyright Nature Publishing Group Sep 2018</rights><rights>European Society of Human Genetics 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c493t-ffe239453950c84b8e78d7c365c35d3b5b75d51bf047d680436ddb7c470332433</citedby><cites>FETCH-LOGICAL-c493t-ffe239453950c84b8e78d7c365c35d3b5b75d51bf047d680436ddb7c470332433</cites><orcidid>0000-0002-2387-9973 ; 0000-0003-3624-2354 ; 0000-0003-0396-7981</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117343/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117343/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29891882$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brancati, Francesco</creatorcontrib><creatorcontrib>Camerota, Letizia</creatorcontrib><creatorcontrib>Colao, Emma</creatorcontrib><creatorcontrib>Vega-Warner, Virginia</creatorcontrib><creatorcontrib>Zhao, Xiangzhong</creatorcontrib><creatorcontrib>Zhang, Ruixiao</creatorcontrib><creatorcontrib>Bottillo, Irene</creatorcontrib><creatorcontrib>Castori, Marco</creatorcontrib><creatorcontrib>Caglioti, Alfredo</creatorcontrib><creatorcontrib>Sangiuolo, Federica</creatorcontrib><creatorcontrib>Novelli, Giuseppe</creatorcontrib><creatorcontrib>Perrotti, Nicola</creatorcontrib><creatorcontrib>Otto, Edgar A</creatorcontrib><creatorcontrib>Undiagnosed Disease Network Italy</creatorcontrib><title>Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome</title><title>European journal of human genetics : EJHG</title><addtitle>Eur J Hum Genet</addtitle><description>A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.</description><subject>Adult</subject><subject>Alleles</subject><subject>Bone dysplasia</subject><subject>Codon, Nonsense</subject><subject>Fibrosis</subject><subject>Heredity</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Hypopituitarism</subject><subject>Hypopituitarism - genetics</subject><subject>Hypopituitarism - pathology</subject><subject>Lethality</subject><subject>Liver</subject><subject>Male</subject><subject>Membrane Proteins - genetics</subject><subject>Mutation, Missense</subject><subject>Nephronophthisis</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Retinitis</subject><subject>Retinitis pigmentosa</subject><subject>Retinitis Pigmentosa - genetics</subject><subject>Retinitis Pigmentosa - pathology</subject><subject>RNA Splicing</subject><subject>Skeleton</subject><subject>Splicing</subject><issn>1018-4813</issn><issn>1476-5438</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNpdkU1LxDAQhoMorq7-AC8S8OKlmnTy1Yug4hesCn4cPIU0TddIt9WkFfbf27rroh6GGXjfeZnhQWiPkiNKQB1HRhnQhFA1FCRiDW1RJkXCGaj1fh4UpiiM0HaMb4T0oqSbaJRmKqNKpVvo7MybqnKVt_jTBG_qNmJf4_bVYesrb8IcT13t8NPtxa2Q2JouOvxw_XL3iOO8LkIzcztoozRVdLvLPkbPlxdP59fJ5P7q5vx0kliWQZuUpUshYxwyTqxiuXJSFdKC4BZ4ATnPJS84zUvCZCEUYSCKIpeWSQKQMoAxOlnkvnf5zBXW1W0wlX4PftafqRvj9V-l9q962nxqQamE74DDZUBoPjoXWz3z0bqqMrVruqhTwlnGgVDRWw_-Wd-aLtT9e70rk1xkqicwRnThsqGJMbhydQwleiCkF4R0z2Eo0EPy_u8vVhs_SOALLwGJ9A</recordid><startdate>20180901</startdate><enddate>20180901</enddate><creator>Brancati, Francesco</creator><creator>Camerota, Letizia</creator><creator>Colao, Emma</creator><creator>Vega-Warner, Virginia</creator><creator>Zhao, Xiangzhong</creator><creator>Zhang, Ruixiao</creator><creator>Bottillo, Irene</creator><creator>Castori, Marco</creator><creator>Caglioti, Alfredo</creator><creator>Sangiuolo, Federica</creator><creator>Novelli, Giuseppe</creator><creator>Perrotti, Nicola</creator><creator>Otto, Edgar A</creator><general>Nature Publishing Group</general><general>Springer International Publishing</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2387-9973</orcidid><orcidid>https://orcid.org/0000-0003-3624-2354</orcidid><orcidid>https://orcid.org/0000-0003-0396-7981</orcidid></search><sort><creationdate>20180901</creationdate><title>Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome</title><author>Brancati, Francesco ; Camerota, Letizia ; Colao, Emma ; Vega-Warner, Virginia ; Zhao, Xiangzhong ; Zhang, Ruixiao ; Bottillo, Irene ; Castori, Marco ; Caglioti, Alfredo ; Sangiuolo, Federica ; Novelli, Giuseppe ; Perrotti, Nicola ; Otto, Edgar A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-ffe239453950c84b8e78d7c365c35d3b5b75d51bf047d680436ddb7c470332433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Alleles</topic><topic>Bone dysplasia</topic><topic>Codon, Nonsense</topic><topic>Fibrosis</topic><topic>Heredity</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Hypopituitarism</topic><topic>Hypopituitarism - genetics</topic><topic>Hypopituitarism - pathology</topic><topic>Lethality</topic><topic>Liver</topic><topic>Male</topic><topic>Membrane Proteins - genetics</topic><topic>Mutation, Missense</topic><topic>Nephronophthisis</topic><topic>Phenotype</topic><topic>Phenotypes</topic><topic>Retinitis</topic><topic>Retinitis pigmentosa</topic><topic>Retinitis Pigmentosa - genetics</topic><topic>Retinitis Pigmentosa - pathology</topic><topic>RNA Splicing</topic><topic>Skeleton</topic><topic>Splicing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brancati, Francesco</creatorcontrib><creatorcontrib>Camerota, Letizia</creatorcontrib><creatorcontrib>Colao, Emma</creatorcontrib><creatorcontrib>Vega-Warner, Virginia</creatorcontrib><creatorcontrib>Zhao, Xiangzhong</creatorcontrib><creatorcontrib>Zhang, Ruixiao</creatorcontrib><creatorcontrib>Bottillo, Irene</creatorcontrib><creatorcontrib>Castori, Marco</creatorcontrib><creatorcontrib>Caglioti, Alfredo</creatorcontrib><creatorcontrib>Sangiuolo, Federica</creatorcontrib><creatorcontrib>Novelli, Giuseppe</creatorcontrib><creatorcontrib>Perrotti, Nicola</creatorcontrib><creatorcontrib>Otto, Edgar A</creatorcontrib><creatorcontrib>Undiagnosed Disease Network Italy</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European journal of human genetics : EJHG</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brancati, Francesco</au><au>Camerota, Letizia</au><au>Colao, Emma</au><au>Vega-Warner, Virginia</au><au>Zhao, Xiangzhong</au><au>Zhang, Ruixiao</au><au>Bottillo, Irene</au><au>Castori, Marco</au><au>Caglioti, Alfredo</au><au>Sangiuolo, Federica</au><au>Novelli, Giuseppe</au><au>Perrotti, Nicola</au><au>Otto, Edgar A</au><aucorp>Undiagnosed Disease Network Italy</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome</atitle><jtitle>European journal of human genetics : EJHG</jtitle><addtitle>Eur J Hum Genet</addtitle><date>2018-09-01</date><risdate>2018</risdate><volume>26</volume><issue>9</issue><spage>1266</spage><epage>1271</epage><pages>1266-1271</pages><issn>1018-4813</issn><eissn>1476-5438</eissn><abstract>A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>29891882</pmid><doi>10.1038/s41431-018-0183-6</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-2387-9973</orcidid><orcidid>https://orcid.org/0000-0003-3624-2354</orcidid><orcidid>https://orcid.org/0000-0003-0396-7981</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | European journal of human genetics : EJHG, 2018-09, Vol.26 (9), p.1266-1271 |
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| source | Springer Link; PubMed Central |
| subjects | Adult Alleles Bone dysplasia Codon, Nonsense Fibrosis Heredity Heterozygote Humans Hypopituitarism Hypopituitarism - genetics Hypopituitarism - pathology Lethality Liver Male Membrane Proteins - genetics Mutation, Missense Nephronophthisis Phenotype Phenotypes Retinitis Retinitis pigmentosa Retinitis Pigmentosa - genetics Retinitis Pigmentosa - pathology RNA Splicing Skeleton Splicing |
| title | Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome |
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