{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:16:18Z","timestamp":1776644178248,"version":"3.51.2"},"reference-count":32,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mitochondrial protein synthesis requires three elongation factors including EF\u2010Tu (<jats:italic>TUFM<\/jats:italic>; OMIM 602389), EF\u2010Ts (<jats:italic>TSFM<\/jats:italic>; OMIM 604723), and EF\u2010G1 (<jats:italic>GFM1<\/jats:italic>; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in <jats:italic>GFM1<\/jats:italic> located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G\u2009&gt;\u2009A; p.Val137Met) and paternal (NM_001308164.1:c.1880G\u2009&gt;\u2009A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as \u201clikely\u2010pathogenic\u201d according to the recommendation of ACMG\/AMP guideline. <jats:italic>GFM1<\/jats:italic> alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10\u201317\u2009years, without developing any life\u2010threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical\u2010by\u2010descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of <jats:italic>GFM1<\/jats:italic> gene.<\/jats:p>","DOI":"10.1002\/ajmg.a.62856","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T08:34:53Z","timestamp":1655282093000},"page":"2693-2700","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Whole exome sequencing identifies a novel compound heterozygous <i>GFM1<\/i> variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family"],"prefix":"10.1002","volume":"188","author":[{"given":"Atta Ullah","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Medicine Pak International Medical College Hayatabad Phase 5  Peshawar Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ibrar","family":"Khan","sequence":"additional","affiliation":[{"name":"Rare Disease Genetics and Genomics Centre for Omic Sciences  Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Ismail","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Zoology Islamia College Peshawar  Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Latif","sequence":"additional","affiliation":[{"name":"Centre for Genetics and Inherited Diseases (CGID) Taibah University  Madinah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Imran","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Radiology Department North West General Hospital and Research Center  Peshawar Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shafi Ullah","family":"Khan","sequence":"additional","affiliation":[{"name":"School of Pharmacy Monash University Malaysia Jalan Lagoon Selatan Bandar Sunway 47500 Selangor  Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thet Thet","family":"Htar","sequence":"additional","affiliation":[{"name":"School of Pharmacy Monash University Malaysia Jalan Lagoon Selatan Bandar Sunway 47500 Selangor  Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghazala","family":"Wahid","sequence":"additional","affiliation":[{"name":"Department of Radiology Hayatabad Medical Complex  Peshawar Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ikram","family":"Ullah","sequence":"additional","affiliation":[{"name":"International Islamic University, Sulaiman Bin Abdullah Aba Al\u2010Khail Centre for Interdisciplinary Research in Basic Sciences International Islamic University  Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fehmida","family":"Bibi","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Special Infectious Agents Unit, King Fahd Medical Research Centre King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asifullah","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Abdul Wali Khan University Mardan (AWKUM)  Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Imran","family":"Naseer","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Center of Excellence in Genomic Medicine Research King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Go Hun","family":"Seo","sequence":"additional","affiliation":[{"name":"3billion Inc.  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