{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:07:12Z","timestamp":1785838032919,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neurodevelopmental disorders (NDDs) with ataxia are genetically heterogeneous and remain a diagnostic challenge. Recent advances in genomic technologies have facilitated the identification of rare, potentially causative variants in genes not traditionally associated with classic NDD phenotypes. The DNAH14 gene, encoding a dynein axonemal heavy chain involved in ciliary motility, has recently emerged as a novel candidate in neurological syndromes. Here, we report two Turkish siblings presenting with late-onset balance disorder, progressive ataxia, and cognitive impairment. Initial genetic analysis revealed that both siblings also harbor FXN GAA repeat expansions consistent with pathogenic Friedreich\u2019s ataxia (FRDA). To elucidate the molecular basis of the patients\u2019 cognitive impairment, whole-exome sequencing was performed. This analysis identified a novel homozygous frameshift variant in the DNAH14 gene, located within the conserved linker domain upstream of the motor core, which is critical for ATP hydrolysis and microtubule interactions. The variant is absent from population databases, predicted to be deleterious by multiple in silico algorithms, and segregates in the family in a manner consistent with autosomal recessive inheritance. The coexistence of FRDA expansions and a truncating DNAH14 variant suggests a potential dual genetic contribution to the observed phenotype, in which FRDA-associated pathology likely underlies the ataxia, while DNAH14 disruption may contribute to additional neurodevelopmental features. This is the first report describing the co-occurrence of FRDA and a homozygous truncating DNAH14 variant in the same individuals, broadening our understanding of overlapping neurogenetic mechanisms. Our findings expand the phenotypic spectrum of DNAH14-related disorders and highlight the importance of considering multilocus pathogenic variants in patients with complex or atypical ataxia presentations.<\/jats:p>","DOI":"10.3390\/ijms27020575","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T12:35:47Z","timestamp":1767702947000},"page":"575","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Biallelic Truncating DNAH14 Variant in Siblings with Neurodevelopmental Disorder and Predominant Ataxia: Clinical Report and Literature Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Savas","family":"Baris","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Ayd\u0131n Maternity and Children\u2019s Hospital, Aydin 09020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0464-6565","authenticated-orcid":false,"given":"Mustafa","family":"Dogan","sequence":"additional","affiliation":[{"name":"Division of Genetics, Gelisim Medical Laboratories, Istanbul 34100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9964-6383","authenticated-orcid":false,"given":"Kerem","family":"Terali","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Cyprus Health and Social Sciences University, Morphou 99750, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2432-9279","authenticated-orcid":false,"given":"Alper","family":"Gezdirici","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Health Sciences Basaksehir Cam and Sakura State Hospital, Istanbul 34480, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Recep","family":"Eroz","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Aksaray University, Aksaray 68100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peren Perk","family":"Yucel","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Basaksehir Cam and Sakura State Hospital, Istanbul 34480, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1987-507X","authenticated-orcid":false,"given":"Huseyin","family":"Kilic","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul 34098, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1597-5922","authenticated-orcid":false,"given":"Cuneyd","family":"Yavas","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Biruni University, Istanbul 34015, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6546-5306","authenticated-orcid":false,"given":"Gizem","family":"Yildirim","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Health Sciences Basaksehir Cam and Sakura State Hospital, Istanbul 34480, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Baris","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Koc University, Istanbul 34450, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a036533","DOI":"10.1101\/cshperspect.a036533","article-title":"Genetic Counseling in Neurodevelopmental Disorders","volume":"10","author":"Blesson","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1097\/WCO.0000000000000710","article-title":"What are neurodevelopmental disorders?","volume":"32","author":"Ismail","year":"2019","journal-title":"Curr. Opin. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.ajhg.2015.11.024","article-title":"Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules","volume":"98","author":"Kochinke","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1038\/s41588-024-01836-1","article-title":"Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings","volume":"56","author":"Schmidt","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1006\/geno.1996.0422","article-title":"Multiple mouse chromosomal loci for dynein-based motility","volume":"36","author":"Vaughan","year":"1996","journal-title":"Genomics"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Despotes, K.A., Zariwala, M.A., Davis, S.D., and Ferkol, T.W. (2024). Primary Ciliary Dyskinesia: A Clinical Review. Cells, 13.","DOI":"10.3390\/cells13110974"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s13059-015-0681-6","article-title":"Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families","volume":"16","author":"Shamseldin","year":"2015","journal-title":"Genome Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1111\/cge.14590","article-title":"Genetics of 67 patients of suspected primary ciliary dyskinesia from India","volume":"106","author":"Jat","year":"2024","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1016\/j.chest.2021.02.006","article-title":"Clinical and Genetic Spectrum of Children With Primary Ciliary Dyskinesia in China","volume":"159","author":"Guan","year":"2021","journal-title":"Chest"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4409","DOI":"10.1016\/j.cell.2022.10.009","article-title":"Genomic architecture of autism from comprehensive whole-genome sequence annotation","volume":"185","author":"Trost","year":"2022","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1002\/humu.24386","article-title":"DNAH14 variants are associated with neurodevelopmental disorders","volume":"43","author":"Li","year":"2022","journal-title":"Hum. Mutat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18862","DOI":"10.1038\/s41598-022-22036-z","article-title":"The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families","volume":"12","author":"Bruwer","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/cge.13438","article-title":"Reanalysis of exome sequencing data of intellectual disability samples: Yields and benefits","volume":"94","author":"Zadjali","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1136\/neurintsurg-2020-016469","article-title":"Exome sequencing of 112 trios identifies recessive genetic variants in brain arteriovenous malformations","volume":"13","author":"Zhang","year":"2021","journal-title":"J. Neurointerv. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.3171\/2015.6.JNS15162","article-title":"Panventriculomegaly with a wide foramen of Magendie and large cisterna magna","volume":"124","author":"Kageyama","year":"2016","journal-title":"J. Neurosurg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1017\/S1355617720000958","article-title":"Longitudinal Study of Cognitive Functioning in Friedreich\u2019s Ataxia","volume":"27","author":"Medler","year":"2021","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e219","DOI":"10.1016\/j.ejpn.2017.04.1133","article-title":"WES in nonprogressive congenital ataxia: Diagnostic yield and identification of novel loci","volume":"21","author":"Macaya","year":"2017","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S1525-1578(10)60523-5","article-title":"Triplet repeat primed PCR (TP PCR) in molecular diagnostic testing for Friedreich ataxia","volume":"6","author":"Ciotti","year":"2004","journal-title":"J. Mol. Diagn."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nature10955","article-title":"The 2.8 A crystal structure of the dynein motor domain","volume":"484","author":"Kon","year":"2012","journal-title":"Nature"},{"key":"ref_21","first-page":"D913","article-title":"Gene4Denovo: An integrated database and analytic platform for de novo mutations in humans","volume":"48","author":"Zhao","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1093\/hmg\/ddh219","article-title":"Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation","volume":"13","author":"Pagenstecher","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12987-021-00265-0","article-title":"The regulatory roles of motile cilia in CSF circulation and hydrocephalus","volume":"18","author":"Kumar","year":"2021","journal-title":"Fluids Barriers CNS"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neuron.2021.12.009","article-title":"Brain ventricles as windows into brain development and disease","volume":"110","author":"Duy","year":"2022","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3355","DOI":"10.1007\/s00381-021-05194-9","article-title":"Ependymal ciliary motion and their role in congenital hydrocephalus","volume":"37","author":"Sakamoto","year":"2021","journal-title":"Child\u2019s Nerv. Syst."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105913","DOI":"10.1016\/j.nbd.2022.105913","article-title":"Rethinking the cilia hypothesis of hydrocephalus","volume":"175","author":"Duy","year":"2022","journal-title":"Neurobiol. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.neuron.2016.05.026","article-title":"Dynein\u2019s Life in the Slow Lane","volume":"90","author":"Roy","year":"2016","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eaat7615","DOI":"10.1126\/science.aat7615","article-title":"Integrative functional genomic analysis of human brain development and neuropsychiatric risks","volume":"362","author":"Li","year":"2018","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e1768","DOI":"10.1002\/mgg3.1768","article-title":"Phenotypes and genotypes in non-consanguineous and consanguineous primary microcephaly: High incidence of epilepsy","volume":"9","author":"Duerinckx","year":"2021","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2814","DOI":"10.1161\/CIRCULATIONAHA.106.649038","article-title":"Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia","volume":"115","author":"Kennedy","year":"2007","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1378\/chest.13-1704","article-title":"Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: Insights into situs ambiguus and heterotaxy","volume":"146","author":"Shapiro","year":"2014","journal-title":"Chest"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/S2213-2600(19)30374-1","article-title":"Primary ciliary dyskinesia in the genomics age","volume":"8","author":"Lucas","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1513\/AnnalsATS.202206-487OC","article-title":"Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype","volume":"20","author":"Barber","year":"2023","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.neuron.2015.12.008","article-title":"The cellular and molecular landscapes of the developing human central nervous system","volume":"89","author":"Silbereis","year":"2016","journal-title":"Neuron"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"dev170100","DOI":"10.1242\/dev.170100","article-title":"Characterization of the ventricular-subventricular stem cell niche during human brain development","volume":"145","author":"Coletti","year":"2018","journal-title":"Development"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1523\/JNEUROSCI.1108-04.2005","article-title":"Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis","volume":"25","author":"Spassky","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1038\/s41591-020-1090-2","article-title":"Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus","volume":"26","author":"Jin","year":"2020","journal-title":"Nat. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41392-024-01809-0","article-title":"Induced pluripotent stem cells (iPSCs): Molecular mechanisms of induction and applications","volume":"9","author":"Cerneckis","year":"2024","journal-title":"Signal Transduct. Target. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/575\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T12:36:39Z","timestamp":1767702999000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/575"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27020575"],"URL":"https:\/\/doi.org\/10.3390\/ijms27020575","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]}}}