title: Compound heterozygous NEK1 variants in two siblings with oral-facial-digital syndrome type II (Mohr syndrome).
abstract: The oral-facial-digital (OFD) syndromes comprise a group of related disorders with a combination of oral, facial and digital anomalies. Variants in several ciliary genes have been associated with subtypes of OFD syndrome, yet in most OFD patients the underlying cause remains unknown. We investigated the molecular basis of disease in two brothers with OFD type II, Mohr syndrome, by performing single-nucleotide polymorphism (SNP)-array analysis on the brothers and their healthy parents to identify homozygous regions and candidate genes. Subsequently, we performed whole-exome sequencing (WES) on the family. Using WES, we identified compound heterozygous variants c.[464G>C];[1226G>A] in NIMA (Never in Mitosis Gene A)-Related Kinase 1 (NEK1). The novel variant c.464G>C disturbs normal splicing in an essential region of the kinase domain. The nonsense variant c.1226G>A, p.(Trp409*), results in nonsense-associated alternative splicing, removing the first coiled-coil domain of NEK1. Candidate variants were confirmed with Sanger sequencing and alternative splicing assessed with cDNA analysis. Immunocytochemistry was used to assess cilia number and length. Patient-derived fibroblasts showed severely reduced ciliation compared with control fibroblasts (18.0 vs 48.9%, P<0.0001), but showed no significant difference in cilia length. In conclusion, we identified compound heterozygous deleterious variants in NEK1 in two brothers with Mohr syndrome. Ciliation in patient fibroblasts is drastically reduced, consistent with a ciliary defect pathogenesis. Our results establish NEK1 variants involved in the etiology of a subset of patients with OFD syndrome type II and support the consideration of including (routine) NEK1 analysis in patients suspected of OFD.
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.|Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Monroe
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Plastic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Isabelle Fpm
authors.initials: IF
authors.lastname: Kappen
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.|Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marijn F
authors.initials: MF
authors.lastname: Stokman
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Paulien A
authors.initials: PA
authors.lastname: Terhal
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marie-José H
authors.initials: MH
authors.lastname: van den Boogaard
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.|Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Sanne Mc
authors.initials: SM
authors.lastname: Savelberg
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Lars T
authors.initials: LT
authors.lastname: van der Veken
authors.affiliation: Department of Oral and Maxillofacial Surgery and Special Dental Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Robert Jj
authors.initials: RJ
authors.lastname: van Es
authors.affiliation: Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Lens
authors.affiliation: Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rutger C
authors.initials: RC
authors.lastname: Hengeveld
authors.affiliation: Department of Oral and Maxillofacial Surgery and Special Dental Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marijn A
authors.initials: MA
authors.lastname: Creton
authors.affiliation: Department of Oral and Maxillofacial Surgery and Special Dental Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nard G
authors.initials: NG
authors.lastname: Janssen
authors.affiliation: Department of Plastic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Aebele B
authors.initials: AB
authors.lastname: Mink van der Molen
authors.affiliation: Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Ebbeling
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, Regenerative Medicine Center-Hubrecht Institute, Utrecht, The Netherlands.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.|Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nine V
authors.initials: NV
authors.lastname: Knoers
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.|Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Gijs
authors.identifier: 0000-0003-3033-0329
authors.initials: G
authors.lastname: van Haaften
mesh_terms: D017398:Alternative Splicing; D002478:Cells, Cultured; D002648:Child; D002923:Cilia / Q000473:pathology; D018389:Codon, Nonsense; D059472:Exome; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D000072380:NIMA-Related Kinase 1 / Q000235:genetics*; D009958:Orofaciodigital Syndromes / Q000235:genetics* / Q000473:pathology; D035781:Siblings
chemical_list: D018389:Codon, Nonsense; C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1