{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T03:29:43Z","timestamp":1776396583351,"version":"3.51.2"},"reference-count":54,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T00:00:00Z","timestamp":1683936000000},"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":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Population diversity is important and rare disease isolates can frequently reveal novel homozygous or biallelic mutations that lead to expanded clinical heterogeneity, with diverse clinical presentations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The present study describes two consanguineous families with a total of seven affected individuals suffering from a clinically similar severe syndromic neurological disorder, with abnormal development and central nervous system (CNS) and peripheral nervous system (PNS) abnormalities. Whole exome sequencing (WES) and Sanger sequencing followed by 3D protein modeling was performed to identify the disease\u2010causing gene. RNA was extracted from the fresh blood of both families affected and healthy individuals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The families were clinically assessed in the field in different regions of Khyber Pakhtunkhwa. Magnetic resonance imagining was obtained in the probands and blood was collected for DNA extraction and WES was performed. Sanger sequencing confirmed a homozygous, likely pathogenic mutation (GRCh38: chr17:42684199G&gt;C; (NM_003632.3): c.333G&gt;C);(NP_003623.1): p.(Trp111Cys) in the <jats:italic>CNTNAP1<\/jats:italic> gene in family A, previously associated with Congenital Hypo myelinating Neuropathy 3 (CHN3; OMIM # 618186) and a novel nonsense variant in family B, (GRCh38: chr16: 57654086C&gt;T; NC_000016.10 (NM_001370440.1): c.721C&gt;T); (NP_001357369.1): p.(Gln241Ter) in the <jats:italic>ADGRG1<\/jats:italic> gene previously associated with bilateral frontoparietal polymicrogyria (OMIM # 606854); both families have extended CNS and PNS clinical manifestations. In addition, 3D protein modeling was performed for the missense variant, p.(Trp111Cys), identified in the <jats:italic>CNTNAP1<\/jats:italic>, suggesting extensive secondary structure changes that might lead to improper function or downstream signaling. No RNA expression was observed in both families affected and healthy individuals hence showing that these genes are not expressed in blood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In the present study, two novel biallelic variants in the <jats:italic>CNTNAP1<\/jats:italic> and <jats:italic>ADGRG1<\/jats:italic> genes in two different consanguineous families with a clinical overlap in the phenotype were identified. Thus, the clinical and mutation spectrum is expanded to provide further evidence that <jats:italic>CNTNAP1<\/jats:italic> and <jats:italic>ADGRG1<\/jats:italic> are very important for widespread neurological development.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.3513","type":"journal-article","created":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T11:39:06Z","timestamp":1683977946000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Overlapping neurological phenotypes in two extended consanguineous families with novel variants in the <i>CNTNAP1<\/i> and <i>ADGRG1<\/i> genes"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5913-8077","authenticated-orcid":false,"given":"Shazia","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Biological Sciences International Islamic University  Islamabad Pakistan"},{"name":"Department of Biochemistry, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University  Islamabad Pakistan"},{"name":"Medical Research, RILD Wellcome Wolfson Centre (Level 4) Royal Devon and Exeter NHS Foundation Trust  Exeter Devon UK"},{"name":"Hafeez Institute of Medical Sciences  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Umair","sequence":"additional","affiliation":[{"name":"Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences Ministry of National Guard Health Affairs (MNGH)  Riyadh Saudi Arabia"},{"name":"Department of Life Sciences, School of Science University of Management and Technology (UMT)  Lahore Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Safdar","family":"Abbas","sequence":"additional","affiliation":[{"name":"Department of Biological Science Dartmouth College  Hanover NH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uroba","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences International Islamic University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gohar","family":"Zaman","sequence":"additional","affiliation":[{"name":"Department of Computer Science Abbottabad University of Science and Technology  Havelian Abbottabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Ansar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Biological Sciences Quaid\u2010i\u2010Azam University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongrong","family":"Wang","sequence":"additional","affiliation":[{"name":"McKusick\u2010Zhang Center for Genetic Medicine, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[{"name":"McKusick\u2010Zhang Center for Genetic Medicine, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College  Beijing China"},{"name":"The Research Center for Medical Genomics China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorder UCL Institute of Neurology  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaurav V.","family":"Harlalka","sequence":"additional","affiliation":[{"name":"Medical Research, RILD Wellcome Wolfson Centre (Level 4) Royal Devon and Exeter NHS Foundation Trust  Exeter Devon UK"},{"name":"Department of Pharmacology Samarth College of Pharmacy  Deulgaon Raja, Dist. 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