{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:58:16Z","timestamp":1792720696233,"version":"4.5.0"},"reference-count":19,"publisher":"Knowledge E DMCC","issue":"6","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"content-domain":{"domain":["knepublishing.com"],"crossmark-restriction":true},"short-container-title":["IJRM"],"abstract":"<jats:p>Background: All considerable families are seeking genetic counseling aiming to manage the next pregnancy according to the positive family history of heterogenetic disorders. Prenatal diagnosis utilizing next-generation sequencing provides a significant means to identify the causes of genetic abnormalities, allowing for timely interventions that support informed family planning. This study explores the power of whole-exome sequencing (WES) in uncovering genetic variants in couples who are seeking genetic counseling for their next pregnancy.\r\nCase Presentations: In this study, WES was used to identify genetic variations associated with disability in families seeking genetic counseling. 3 families who had at least 1 child with developmental delay (DD) and\/or intellectual disability (ID) participated in a genetic counselling clinic, Yazd Reproductive Science Institute, Yazd, Iran to have successful outcomes for the next pregnancy. 3 distinct mutation sites from 3 families were diagnosed, following the WES for affected children with intellectual disabilities. Results showed a homozygous de novo stop-gain mutation in malate dehydrogenase 1 gene (NM_005917.4:c.4C&gt;T; p.Arg2Ter), a splice acceptor mutation in the post-glycosylphosphatidylinositol attachment to proteins inositol deacylase 1 gene (NM_024989.4:c.1221\u20131G&gt;T), and a missense mutation in the lysosomal trafficking regulator gene (NM_000081.4:c.949G&gt;A; p.Glu317Lys) in each family, respectively.\r\nConclusion: For cases with DD and unexplained ID, WES is a very successful diagnostic approach. Unfortunately, large Iranian families exhibit significant genetic heterogeneity, highlighting the critical role of de novo variants in diagnosis. The results of this study confirm that proteins inositol deacylase 1, malate dehydrogenase 1, and lysosomal trafficking regulator are involved in the pathophysiology of ID\/DD and the transformative potential of prenatal genetic screening.<\/jats:p>","DOI":"10.18502\/ijrm.v23i6.19405","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T12:16:52Z","timestamp":1755692212000},"update-policy":"https:\/\/doi.org\/10.18502\/knecrossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Prenatal diagnosis using next-generation sequencing in genetic counseling: Novel mutations in three large Iranian families: A case series"],"prefix":"10.18502","volume":"23","author":[{"given":"Hamidreza","family":"Ashrafzadeh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farzaneh","family":"Tafvizi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasrin","family":"Ghasemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Yahya Vahidi","family":"Mehrjardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vahid","family":"Naseh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"7770","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"286906","doi-asserted-by":"crossref","unstructured":"[1] Schmidt JL, Maas R, Altmeyer SR. 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Nat Methods 2014; 11: 361\u2013362.","DOI":"10.1038\/nmeth.2890"},{"key":"286913","doi-asserted-by":"crossref","unstructured":"[8] Kircher M, Witten DM, Jain P, O\u2019roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 2014; 46: 310\u2013315.","DOI":"10.1038\/ng.2892"},{"key":"286914","doi-asserted-by":"crossref","unstructured":"[9] Jagadeesh KA, Wenger AM, Berger MJ, Guturu H, Stenson PD, Cooper DN, et al. M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet 2016; 48: 1581\u20131586.","DOI":"10.1038\/ng.3703"},{"key":"286915","doi-asserted-by":"crossref","unstructured":"[10] Serra-Vinardell J, Sandler MB, De Pace R, Manzella-Lapeira J, Cougnoux A, Keyvanfar K, et al. LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size. Cell Mol Life Sci 2023; 80: 53.","DOI":"10.1007\/s00018-023-04695-x"},{"key":"286916","doi-asserted-by":"crossref","unstructured":"[11] Song Y, Dong Z, Luo S, Yang J, Lu Y, Gao B, et al. Identification of a compound heterozygote in LYST gene: A case report on Chediak-Higashi syndrome. BMC Med Genet 2020; 21: 4.","DOI":"10.1186\/s12881-019-0922-8"},{"key":"286917","doi-asserted-by":"crossref","unstructured":"[12] Acevedo A, Torres F, Kiwi M, Baeza-Lehnert F, Barros LF, Lee-Liu D, et al. Metabolic switch in the aging astrocyte supported via integrative approach comprising network and transcriptome analyses. Aging 2023; 15: 9896.","DOI":"10.18632\/aging.204663"},{"key":"286918","doi-asserted-by":"crossref","unstructured":"[13] Ait-El-Mkadem S, Dayem-Quere M, Gusic M, Chaussenot A, Bannwarth S, Fran\u00e7ois B, et al. Mutations in MDH2, encoding a Krebs cycle enzyme, cause early-onset severe encephalopathy. Am J Hum Genet 2017; 100: 151\u2013159.","DOI":"10.1016\/j.ajhg.2016.11.014"},{"key":"286919","doi-asserted-by":"crossref","unstructured":"[14] Zuend M, Saab AS, Wyss MT, Ferrari KD, H\u00f6sli L, Looser ZJ, et al. Arousal-induced cortical activity triggers lactate release from astrocytes. Nat Metab 2020; 2: 179\u2013191.","DOI":"10.1038\/s42255-020-0170-4"},{"key":"286920","doi-asserted-by":"crossref","unstructured":"[15] Chen Z, Yuan Z, Yang S, Zhu Y, Xue M, Zhang J, et al. Brain energy metabolism: Astrocytes in neurodegenerative diseases. CNS Neurosci Ther 2023; 29: 24\u201336.","DOI":"10.1111\/cns.13982"},{"key":"286921","doi-asserted-by":"crossref","unstructured":"[16] McNair LM, Andersen JV, Waagepetersen HS. Stable isotope tracing reveals disturbed cellular energy and glutamate metabolism in hippocampal slices of aged male mice. Neurochem Int 2023; 171: 105626.","DOI":"10.1016\/j.neuint.2023.105626"},{"key":"286922","doi-asserted-by":"crossref","unstructured":"[17] Hanse EA, Ruan C, Kachman M, Wang D, Lowman XH, Kelekar A. Cytosolic malate dehydrogenase activity helps support glycolysis in actively proliferating cells and cancer. Oncogene 2017; 36: 3915\u20133924.","DOI":"10.1038\/onc.2017.36"},{"key":"286923","doi-asserted-by":"crossref","unstructured":"[18] Murakami Y, Tawamie H, Maeda Y, B\u00fcttner C, Buchert R, Radwan F, et al. Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy. PLoS Genet 2014; 10: e1004320.","DOI":"10.1371\/journal.pgen.1004320"},{"key":"286924","doi-asserted-by":"crossref","unstructured":"[19] Kettwig M, Elpeleg O, Wegener E, Dreha-Kulaczewski S, Henneke M, G\u00e4rtner J, et al. Compound heterozygous variants in PGAP1 causing severe psychomotor retardation, brain atrophy, recurrent apneas and delayed myelination: A case report and literature review. 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