{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:27:18Z","timestamp":1782275238432,"version":"3.54.5"},"reference-count":15,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T00:00:00Z","timestamp":1640908800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006259","name":"Teva Pharmaceutical Industries","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006259","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>We aimed to determine the molecular and biochemical basis of an extended highly consanguineous family with multiple children presenting severe congenital hypotonia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Clinical investigations, homozygosity mapping, linkage analyses and whole exome sequencing, were performed. mRNA and protein levels were determined. Population screening was followed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We have identified a novel nonsense variant in <jats:italic>NGLY1<\/jats:italic> in two affected siblings, and compound heterozygosity for three novel <jats:italic>RYR1<\/jats:italic> variants in two affected sisters from another nuclear family within the broad pedigree. Population screening revealed a high prevalence of carriers for both diseases. The genetic variants were proven to be pathogenic, as demonstrated by western blot analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Revealing the genetic diagnosis enabled us to provide credible genetic counselling and pre\u2010natal diagnosis to the extended family and genetic screening for this high\u2010risk population. Whole exome\/genome sequencing should be the first tier tool for accurate determination of the genetic basis of congenital hypotonia. Two different genetic disorders within a large consanguineous pedigree should be always considered.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1849","type":"journal-article","created":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T09:05:35Z","timestamp":1640941535000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Congenital Hypotonia: Cracking a SAGA of consanguineous kindred harboring four genetic variants"],"prefix":"10.1002","volume":"10","author":[{"given":"Limor","family":"Kalfon","sequence":"first","affiliation":[{"name":"Institute of Human Genetics Galilee Medical Center Nahariya Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meirav","family":"Baydany","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Galilee Medical Center Nahariya Israel"},{"name":"The Azrieli Faculty of Medicine Bar Ilan Safed Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadra","family":"Samra","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Galilee Medical Center Nahariya Israel"},{"name":"The Azrieli Faculty of Medicine Bar Ilan Safed Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nawaf","family":"Heno","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Galilee Medical Center Nahariya Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zvi","family":"Segal","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Galilee Medical Center Nahariya Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayelet","family":"Eran","sequence":"additional","affiliation":[{"name":"Neuroradiology Rambam Health Care Campus, and Technion Faculty of Medicine Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alon","family":"Yulevich","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Galilee Medical Center Nahariya Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yakov","family":"Fellig","sequence":"additional","affiliation":[{"name":"Department of Pathology Hadassah Hebrew University Medical Center Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5230-4247","authenticated-orcid":false,"given":"Hanna","family":"Mandel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Galilee Medical Center Nahariya Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0065-1922","authenticated-orcid":false,"given":"Tzipora C.","family":"Falik\u2010Zaccai","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Galilee Medical Center Nahariya Israel"},{"name":"The Azrieli Faculty of Medicine Bar Ilan Safed Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,31]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2011.10.010"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.232850"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0191228"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.22"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e318217477f"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20102\u201031"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2017.191"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0146040"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.75"},{"key":"e_1_2_9_11_1","first-page":"1993","volume-title":"GeneReviews\u00ae [Internet]","author":"Lam C."},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2016.08.002"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(17)30875\u20109"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clp.2015.02.008"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12732"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100039\u20101677734"}],"container-title":["Molecular Genetics &amp; 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