title: A novel missense mutation in the NSDHL gene identified in a Lithuanian family by targeted next-generation sequencing causes CK syndrome.
abstract: The NSDHL gene encodes 3β-hydroxysteroid dehydrogenase involved in one of the later steps of the cholesterol biosynthetic pathway. Mutations in this gene can cause CHILD syndrome (OMIM 308050) and CK syndrome (OMIM 300831). CHILD syndrome is an X-linked dominant, male lethal disorder caused by mutations in the NSDHL gene that result in the loss of the function of the NSDHL protein. CK syndrome is an allelic X-linked recessive disorder. So far, 13 patients with CK syndrome from two families have been reported on. We present a new five-generation family with affected males manifesting clinical features of CK syndrome. Next generation sequencing was targeted to a custom panel of 542 genes with known or putative implication on intellectual disability. Missense mutation p.Gly152Asp was identified in the NSDHL gene in the DNA sample of the affected male. Mutation carrier status was confirmed for all the obligate carriers in the family. The clinical features of the affected males in the family manifested as weak fetal movements, severe intellectual disability, seizures, spasticity, atrophy of optic discs, microcephaly, plagiocephaly, skeletal abnormalities, and minor facial anomalies, including a high nasal bridge, strabismus, and micrognathia. A highly significant preferential transmission of the mutation was observed in this and previous families segregating CK syndrome. Our report expands the clinical spectrum of this syndrome to include weak fetal movements, spasticity, and plagiocephaly, and transmission ratio distortion. The various findings in these patients increase our understanding of the diversity of the clinical presentation of cholesterol biosynthesis disorders.
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
authors.forename: Egle
authors.initials: E
authors.lastname: Preiksaitiene
authors.affiliation: Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Caro
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
authors.forename: Eglė
authors.initials: E
authors.lastname: Benušienė
authors.affiliation: Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Silvestre
authors.initials: S
authors.lastname: Oltra
authors.affiliation: Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Orellana
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
authors.forename: Aušra
authors.initials: A
authors.lastname: Morkūnienė
authors.affiliation: Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Mónica Pilar
authors.initials: MP
authors.lastname: Roselló
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
authors.forename: Jurate
authors.initials: J
authors.lastname: Kasnauskiene
authors.affiliation: Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Monfort
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
authors.forename: Vaidutis
authors.initials: V
authors.lastname: Kučinskas
authors.affiliation: Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mayo
authors.affiliation: Unidad de Genética, Grupo de Investigación Traslacional en Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Martinez
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000483:Alleles; D004830:Epilepsy, Tonic-Clonic / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008097:Lithuania; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D015096:3-Hydroxysteroid Dehydrogenases; C478776:Nsdhl protein, human
keywords: CHILD syndrome; CK syndrome; NSDHL gene; X-linked intellectual disability; p.Gly152Asp mutation