{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T07:26:22Z","timestamp":1763018782972,"version":"3.41.0"},"reference-count":36,"publisher":"Scientific Scholar","content-domain":{"domain":["ijmr.org.in"],"crossmark-restriction":true},"short-container-title":["Indian J Med Res"],"abstract":"<jats:sec>\n<jats:title>Background &amp; objectives<\/jats:title>\n<jats:p>Prenatal ultrasonography in the first and second trimesters detects foetal structural anomalies in up to five per cent of pregnancies. These anomalies are often suspected to have a genetic cause. While conventional genetic tests such as karyotyping, fluorescent <jats:italic>in situ<\/jats:italic> hybridisation (FISH), and chromosomal microarray (CMA) have been used alongside whole-exome sequencing (WES), their combined diagnostic yield in malformed foetuses is limited to 40 per cent, leaving most cases undiagnosed. This study aimed to identify novel genetic factors linked to foetal structural malformations.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>A total of 44 medically terminated foetuses were included in this study with severe structural malformations from a maternity hospital in the western part of India. We performed a comprehensive genetic analysis of products of conception (POC) employing karyotyping, FISH, CMA (750K resolution) and WES. Further, in cases with inconclusive genetic findings, we reanalysed the WES data using our in-house analysis pipeline and Exomiser (v13.2.1).<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Genetic anomalies identified among the 44 foetuses included trisomy 21 (n=4), trisomy 13 (n=3), and XXY mosaicism 47 (n=1) in 18.1 per cent (8 out of 44) of the cases. Further, CMA identified CNVs in 13.6 per cent (n=6) cases, of which five cases showed pathogenic CNVs. With the inclusion of WES, the diagnostic yield increased by 4.5 per cent. We reanalysed the WES data and identified six potential candidates, including <jats:italic>RUNX2<\/jats:italic> (spinal dysraphism), <jats:italic>PALLD<\/jats:italic> (Arnold-Chiari malformation), <jats:italic>KMT2D<\/jats:italic> (Holoprosencephaly), <jats:italic>FBN2<\/jats:italic> (structural heart and spine defects), <jats:italic>CPLANE1<\/jats:italic> (Dandy-Walker malformation), and <jats:italic>KMD1A<\/jats:italic> (structural brain abnormality).<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Interpretation &amp; conclusions<\/jats:title>\n<jats:p>This study summarises the findings of genetic evaluation of malformed foetuses in a low-resource setting, which caters to low-income groups of society. The candidate genes reported in this study offer scope for functional studies in relevant animal models to establish genotype-phenotype correlation.<\/jats:p>\n<\/jats:sec>","DOI":"10.25259\/ijmr_1318_2024","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T18:04:55Z","timestamp":1751306695000},"page":"510-520","update-policy":"https:\/\/doi.org\/10.25259\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exome sequencing uncovers promising candidate genes for foetal structural malformations"],"prefix":"10.25259","volume":"161","author":[{"given":"Digumarthi V.S.","family":"Sudhakar","sequence":"first","affiliation":[{"name":"Department of Genetic Research Centre, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaini","family":"Joseph","sequence":"additional","affiliation":[{"name":"Department of Genetic Research Centre, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vandana","family":"Bansal","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Nowrosjee Wadia Maternity Hospital, Mumbai, Maharashtra, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akshay","family":"Gangurde","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Nowrosjee Wadia Maternity Hospital, Mumbai, Maharashtra, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neha","family":"Nitin Minde","sequence":"additional","affiliation":[{"name":"Department of Genetic Research Centre, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harshvardhan","family":"Gawde","sequence":"additional","affiliation":[{"name":"Department of Genetic Research Centre, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shailesh Shankar","family":"Pande","sequence":"additional","affiliation":[{"name":"Department of Genetic Research Centre, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"10894","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"10.25259\/IJMR_1318_2024\/ref-1","doi-asserted-by":"crossref","first-page":"j2563","DOI":"10.1136\/bmj.j2563","article-title":"Risk of major congenital malformations in relation to maternal overweight and obesity severity: Cohort study of 1.2 million singletons","volume":"357","author":"Persson","year":"2017","journal-title":"BMJ"},{"key":"10.25259\/IJMR_1318_2024\/ref-2","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.ajhg.2023.07.010","article-title":"Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and foetal structural anomalies","volume":"110","author":"Lowther","year":"2023","journal-title":"Am J Hum Genet"},{"key":"10.25259\/IJMR_1318_2024\/ref-3","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/gim.2017.111","article-title":"Molecular autopsy in maternal-foetal medicine","volume":"20","author":"Shamseldin","year":"2018","journal-title":"Genet Med"},{"key":"10.25259\/IJMR_1318_2024\/ref-4","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1056\/NEJMoa1203382","article-title":"Chromosomal microarray versus karyotyping for prenatal diagnosis","volume":"367","author":"Wapner","year":"2012","journal-title":"N Engl J Med"},{"key":"10.25259\/IJMR_1318_2024\/ref-5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1002\/pd.5102","article-title":"Promises, pitfalls and practicalities of prenatal whole exome sequencing","volume":"38","author":"Best","year":"2018","journal-title":"Prenat Diagn"},{"key":"10.25259\/IJMR_1318_2024\/ref-6","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/s41431-018-0324-y","article-title":"Exome sequencing of foetal anomaly syndromes: Novel phenotype-genotype discoveries","volume":"27","author":"Meier","year":"2019","journal-title":"Eur J Hum Genet"},{"key":"10.25259\/IJMR_1318_2024\/ref-7","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S0140-6736(18)31940-8","article-title":"Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study","volume":"393","author":"Lord","year":"2019","journal-title":"Lancet"},{"key":"10.25259\/IJMR_1318_2024\/ref-8","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s13073-022-01130-x","article-title":"Application of exome sequencing for prenatal diagnosis of foetal structural anomalies: Clinical experience and lessons learned from a cohort of 1618 fetuses","volume":"14","author":"Fu","year":"2022","journal-title":"Genome Med"},{"key":"10.25259\/IJMR_1318_2024\/ref-9","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/uog.18915","article-title":"Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities","volume":"51","author":"Fu","year":"2018","journal-title":"Ultrasound Obstet Gynecol"},{"key":"10.25259\/IJMR_1318_2024\/ref-10","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ajog.2022.08.040","article-title":"Prenatal exome and genome sequencing for foetal structural abnormalities","volume":"228","author":"Vora","year":"2023","journal-title":"Am J Obstet Gynecol"},{"key":"10.25259\/IJMR_1318_2024\/ref-11","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1038\/gim.2018.30","article-title":"Rapid prenatal diagnosis using targeted exome sequencing: A cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management","volume":"20","author":"Chandler","year":"2018","journal-title":"Genet Med"},{"key":"10.25259\/IJMR_1318_2024\/ref-12","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0140-6736(71)90287-X","article-title":"A rapid banding technique for human chromosomes","volume":"2","author":"Seabright","year":"1971","journal-title":"Lancet"},{"key":"10.25259\/IJMR_1318_2024\/ref-13","volume-title":"An international system for human cytogenomic nomenclature (2020) reprint of \u2018cytogenetic and genome research","year":"2020"},{"key":"10.25259\/IJMR_1318_2024\/ref-14","first-page":"885","article-title":"Chromosome 22 microdeletion by F.I.S.H","volume":"73","author":"Gawde","year":"2006","journal-title":"in isolated congenital heart disease. Indian J Pediatr"},{"key":"10.25259\/IJMR_1318_2024\/ref-15","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"10.25259\/IJMR_1318_2024\/ref-16","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1093\/bioinformatics\/btq330","article-title":"Deriving the consequences of genomic variants with the ensembl API and SNP effect predictor","volume":"26","author":"McLaren","year":"2010","journal-title":"Bioinformatics"},{"key":"10.25259\/IJMR_1318_2024\/ref-17","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1200\/CCI.19.00132","article-title":"Integrated informatics analysis of cancer-related variants","volume":"4","author":"Pagel","year":"2020","journal-title":"JCO Clin Cancer Inform"},{"key":"10.25259\/IJMR_1318_2024\/ref-18","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1038\/s41436-021-01242-6","article-title":"Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: An evidence-based clinical guideline of the American college of medical genetics and genomics (ACMG)","volume":"23","author":"Manickam","year":"2021","journal-title":"Genet Med"},{"key":"10.25259\/IJMR_1318_2024\/ref-19","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1093\/hmg\/ddac216","article-title":"Exome sequencing and functional analyses revealed CETN1 variants leads to impaired cell division and male fertility","volume":"32","author":"Sudhakar","year":"2023","journal-title":"Hum Mol Genet"},{"key":"10.25259\/IJMR_1318_2024\/ref-20","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1101\/gr.160325.113","article-title":"Improved exome prioritization of disease genes through cross-species phenotype comparison","volume":"24","author":"Robinson","year":"2014","journal-title":"Genome Res"},{"key":"10.25259\/IJMR_1318_2024\/ref-21","doi-asserted-by":"crossref","first-page":"779237","DOI":"10.3389\/fgene.2021.779237","article-title":"Prenatal diagnosis of 17p11.2 copy number abnormalities associated with smith-magenis and potocki-lupski syndromes in fetuses","volume":"12","author":"Cai","year":"2021","journal-title":"Front Genet"},{"key":"10.25259\/IJMR_1318_2024\/ref-22","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1023\/A:1012758925617","article-title":"Identification of novel CBFA1\/RUNX2 mutations causing cleidocranial dysplasia","volume":"24","author":"Bergwitz","year":"2001","journal-title":"J Inherit Metab Dis"},{"key":"10.25259\/IJMR_1318_2024\/ref-23","doi-asserted-by":"crossref","first-page":"dev187997","DOI":"10.1242\/dev.187997","article-title":"The KMT2D kabuki syndrome histone methylase controls neural crest cell differentiation and facial morphology","volume":"147","author":"Shpargel","year":"2020","journal-title":"Development"},{"key":"10.25259\/IJMR_1318_2024\/ref-24","doi-asserted-by":"crossref","first-page":"256ra135","DOI":"10.1126\/scitranslmed.3009278","article-title":"Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of kabuki syndrome","volume":"6","author":"Bjornsson","year":"2014","journal-title":"Sci Transl Med"},{"key":"10.25259\/IJMR_1318_2024\/ref-25","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/cge.13598","article-title":"Novel heterozygous variants in KMT2D associated with holoprosencephaly","volume":"96","author":"Tekendo-Ngongang","year":"2019","journal-title":"Clin Genet"},{"key":"10.25259\/IJMR_1318_2024\/ref-26","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1534\/g3.117.300292","article-title":"Optimizing genomic methods for mapping and identification of candidate variants in ENU mutagenesis screens using inbred mice","volume":"8","author":"Geister","year":"2018","journal-title":"G3 (Bethesda)"},{"key":"10.25259\/IJMR_1318_2024\/ref-27","doi-asserted-by":"crossref","first-page":"804202","DOI":"10.3389\/fgene.2022.804202","article-title":"Identification of novel FBN2 variants in a cohort of congenital contractural arachnodactyly","volume":"13","author":"Sun","year":"2022","journal-title":"Front Genet"},{"key":"10.25259\/IJMR_1318_2024\/ref-28","doi-asserted-by":"crossref","first-page":"e0155908","DOI":"10.1371\/journal.pone.0155908","article-title":"Identification of a novel missense FBN2 mutation in a Chinese family with congenital contractural arachnodactyly using exome sequencing","volume":"11","author":"Deng","year":"2016","journal-title":"PLoS One"},{"key":"10.25259\/IJMR_1318_2024\/ref-29","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1046\/j.1469-0705.2002.00819.x","article-title":"Prenatal ultrasound findings in a fetus with congenital contractural arachnodactyly","volume":"20","author":"K\u00f6lble","year":"2002","journal-title":"Ultrasound Obstet Gynecol"},{"key":"10.25259\/IJMR_1318_2024\/ref-30","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.ejmg.2018.03.012","article-title":"Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome","volume":"61","author":"Bonnard","year":"2018","journal-title":"Eur J Med Genet"},{"key":"10.25259\/IJMR_1318_2024\/ref-31","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1111\/jcmm.17326","article-title":"Whole-exome sequencing identified novel variants in CPLANE1 that causes oral-facial-digital syndrome \u2165 by inducing primary cilia abnormality","volume":"26","author":"Qian","year":"2022","journal-title":"J Cell Mol Med"},{"key":"10.25259\/IJMR_1318_2024\/ref-32","doi-asserted-by":"crossref","first-page":"1102639","DOI":"10.3389\/fped.2023.1102639","article-title":"Clinical and genetic characteristics of 36 children with Joubert syndrome","volume":"11","author":"Dong","year":"2023","journal-title":"Front Pediatr"},{"key":"10.25259\/IJMR_1318_2024\/ref-33","doi-asserted-by":"crossref","first-page":"16400","DOI":"10.3390\/ijms242216400","article-title":"Genetic heterogeneity underlying phenotypes with early-onset cerebellar atrophy","volume":"24","author":"Mart\u00ednez-Rubio","year":"2023","journal-title":"Int J Mol Sci"},{"key":"10.25259\/IJMR_1318_2024\/ref-34","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/gim.2015.161","article-title":"Gene discovery for mendelian conditions via social networking: De novo variants in KDM1A cause developmental delay and distinctive facial features","volume":"18","author":"Chong","year":"2016","journal-title":"Genet Med"},{"key":"10.25259\/IJMR_1318_2024\/ref-35","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1002\/cm.21754","article-title":"miR96- and miR182-driven regulation of cytoskeleton results in inhibition of glioblastoma motility","volume":"80","author":"Akda\u015f","year":"2023","journal-title":"Cytoskeleton (Hoboken)"},{"key":"10.25259\/IJMR_1318_2024\/ref-36","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.mcn.2004.12.002","article-title":"Disruption of palladin results in neural tube closure defects in mice","volume":"29","author":"Luo","year":"2005","journal-title":"Mol Cell Neurosci"}],"container-title":["The Indian Journal of Medical Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ijmr.org.in\/exome-sequencing-uncovers-promising-candidate-genes-for-foetal-structural-malformations\/","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/ijmr.org.in\/exome-sequencing-uncovers-promising-candidate-genes-for-foetal-structural-malformations\/","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T18:05:00Z","timestamp":1751306700000},"score":1,"resource":{"primary":{"URL":"http:\/\/ijmr.org.in\/exome-sequencing-uncovers-promising-candidate-genes-for-foetal-structural-malformations\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,26]]},"references-count":36,"alternative-id":["10.25259\/IJMR_1318_2024"],"URL":"https:\/\/doi.org\/10.25259\/ijmr_1318_2024","relation":{},"ISSN":["0971-5916"],"issn-type":[{"value":"0971-5916","type":"print"}],"subject":[],"published":{"date-parts":[[2025,6,26]]},"article-number":"510"}}