{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T09:21:32Z","timestamp":1762161692038,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the FAT1 gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic FAT1 variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome\/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.<\/jats:p>","DOI":"10.3390\/genes12070962","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T11:01:38Z","timestamp":1624532498000},"page":"962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples"],"prefix":"10.3390","volume":"12","author":[{"given":"Francesca","family":"Peluso","sequence":"first","affiliation":[{"name":"Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5033-7854","authenticated-orcid":false,"given":"Stefano Giuseppe","family":"Caraffi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Zuntini","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Trimarchi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, 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Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6543-6225","authenticated-orcid":false,"given":"Emanuele","family":"Agolini","sequence":"additional","affiliation":[{"name":"Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7597-940X","authenticated-orcid":false,"given":"Elena","family":"Cellini","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children\u2019s Hospital, University of Florence, 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-8018","authenticated-orcid":false,"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Crisafi","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Napoli","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children\u2019s Hospital, University of Florence, 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9037-4297","authenticated-orcid":false,"given":"Antonio","family":"Novelli","sequence":"additional","affiliation":[{"name":"Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giancarlo","family":"Gargano","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, 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Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/ejhg.2013.167","article-title":"Consanguineous marriage and reproductive risk: Attitudes and understanding of ethnic groups practising consanguinity in western society","volume":"22","author":"Teeuw","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nrg.2017.109","article-title":"Runs of homozygosity: Windows into population history and trait architecture","volume":"19","author":"Ceballos","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.ejmg.2014.09.003","article-title":"First steps in exploring prospective exome sequencing of consanguineous couples","volume":"57","author":"Teeuw","year":"2014","journal-title":"Eur. J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0140-6736(14)60020-9","article-title":"Analysis of the born in Bradford birth cohort\u2013authors\u2019 reply","volume":"383","author":"Sheridan","year":"2014","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13023-018-0763-0","article-title":"Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders","volume":"13","author":"Komlosi","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.ajhg.2019.09.019","article-title":"Lessons learned from large-scale, first-tier clinical exome sequencing in a highly consanguineous population","volume":"105","author":"Monies","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/humu.23149","article-title":"Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes","volume":"38","author":"Parrini","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1038\/nprot.2015.105","article-title":"Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR","volume":"10","author":"Yang","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kopanos, C., Tsiolkas, V., Kouris, A., Chapple, C.E., Albarca Aguilera, M., Meyer, R., and Massouras, A. (2018). VarSome: The human genomic variant search engine. Oxf. Bioinform., bty897.","DOI":"10.1101\/367359"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1016\/j.neuron.2014.12.017","article-title":"Katanin p80 regulates human cortical development by limiting centriole and cilia number","volume":"84","author":"Hu","year":"2014","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1016\/j.neuron.2014.12.014","article-title":"Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors","volume":"84","author":"Caglayan","year":"2014","journal-title":"Neuron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"dev195552","DOI":"10.1242\/dev.195552","article-title":"Hedgehog signaling and the primary cilium: Implications for spatial and temporal constraints on signaling","volume":"148","author":"Ho","year":"2021","journal-title":"Development"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1002\/ajmg.a.37484","article-title":"A syndrome of microcephaly, short stature, polysyndactyly, and dental anomalies caused by a homozygous KATNB1 mutation","volume":"170A","author":"Yigit","year":"2016","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1038\/s41467-019-08547-w","article-title":"Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly","volume":"10","author":"Lahrouchi","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/s41586-020-03046-1","article-title":"Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis","volume":"589","author":"Pastushenko","year":"2021","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10822","DOI":"10.1038\/ncomms10822","article-title":"FAT1 mutations cause a glomerulotubular nephropathy","volume":"7","author":"Gee","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2215\/CJN.06060519","article-title":"Reverse phenotyping after whole-exome sequencing in steroid-resistant nephrotic syndrome","volume":"15","author":"Landini","year":"2020","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s13730-020-00529-y","article-title":"FAT1 biallelic truncating mutation causes a non-syndromic proteinuria in a child","volume":"10","author":"Rossanti","year":"2021","journal-title":"CEN Case Rep."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Haug, P., Koller, S., Maggi, J., Lang, E., Feil, S., Wlodarczyk, A., B\u00e4hr, L., Steindl, K., Rohrbach, M., and Gerth-Kahlert, C. (2021). Whole exome sequencing in coloboma\/ microphthalmia: Identification of novel and recurrent variants in seven genes. Genes, 12.","DOI":"10.3390\/genes12010065"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1126\/science.1248228","article-title":"Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition","volume":"343","author":"Gros","year":"2014","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Boussion, S., Escande, F., Jourdain, A.S., Smol, T., Brunelle, P., Duhamel, C., Alembik, Y., Atti\u00e9-Bitach, T., Baujat, G., and Bazin, A. (2020). TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A. Hum. Mutat., 1220\u20131225.","DOI":"10.1002\/humu.24021"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/humu.22760","article-title":"Identification of variants in the 4q35 Gene FAT1 in patients with a facioscapulohumeral dystrophy-like phenotype","volume":"36","author":"Puppo","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of disease phenotypes resulting from multilocus genomic variation","volume":"376","author":"Posey","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e1360","DOI":"10.1212\/WNL.0000000000008200","article-title":"Subcortical heterotopic gray matter brain malformations: Classification study of 107 individuals","volume":"93","author":"Oegema","year":"2019","journal-title":"Neurology"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/7\/962\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:22:59Z","timestamp":1760163779000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/7\/962"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,24]]},"references-count":26,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["genes12070962"],"URL":"https:\/\/doi.org\/10.3390\/genes12070962","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2021,6,24]]}}}