EGAGenomicsTayfun Ozcelikhttps://ega-archive.org/dacs/EGAC01000000008EGAEGA DAC EGAC01000000008EGAtozcelik@bilkent.edu.trThe biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1-13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans.Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred.Gulsuner Suleyman S, Tekinay Ayse Begum AB, Doerschner Katja K, Boyaci Huseyin H, Bilguvar Kaya K, Unal Hilal H, Ors Aslihan A, Onat O Emre OE, Atalar Ergin E, Basak A Nazli AN, Topaloglu Haluk H, Kansu Tulay T, Tan Meliha M, Tan Uner U, Gunel Murat M, Ozcelik Tayfun Tepilepsy, Locomotor Activities., Congenital cerebellar hypoplasia, Underdeveloped cerebellum, near total absence of cerebellum, Materials, Small cerebellum, Chiari IV malformation, Genetic, Activity, Hypoplastic cerebellum, Gene, Chiari 4 malformation, INSDC_feature:gene, and global developmental delay, subtotal absence of cerebellum, Locomotor Activity, Cistrons, Locomotor, Activities, Material, cerebellar hypoplasia/atrophy, Genetic Materials, cerebellar hypoplasia, Cistron, isolated cerebellar agenesis, Hypoplasia of cerebellum, Genetic Material, congenital cerebellar HypoplasiaNetworks, reticulatum thalami (Hassler), corpus cerebelli, Disorders, Small cerebellum, Chiari IV malformation, Materials, Kinship, single-organism developmental process, Activity, acetylglucosaminyltransferase-like protein, postnatal development, Intellectual Disabilities, epencephalon-1, Poor school performance, Mbp1, DELTA AND GAMMA, growth and development, Imaging, Tomography, congenital defects, betaTub1, aplasia, Resonance Image, Mutations, Chemical Shift Imagings, B1t, diseases, MRI Scans, Magnetic Resonance Imaging, Life Cycle, Chemical, diseases and disorders, AI451093, turkey, myd, nucleus reticularis, Missense, Family Life Cycle, Retardation, Underdeveloped cerebellum, Spin, human disease, Man (Taxonomy), Kinship Network, kus, like-acetylglucosaminyltransferase, Disabilities, beta1tub, CG9277, ERV-R envelope protein, Dull intelligence, hypoplasia, Missense Mutations, Mbp-1, T, beta-particle, Intellectual, chromatid, Diffusions, Neocortical Commissure, SU, 1t, geographical area, Parencephalon, e, infratentorial region, motor cortex (Noback), e-, beta1Tub, NMR, Homo sapiens disease, Functional MRIs, Echo Imaging, Retardations, Family Life Cycles, TM, Functional MRI, Envelope polyprotein, HERV-T Env protein, Intellectual Development Disorder, near total absence of cerebellum, BETA 56D, gyltl1b-b, Modern, Chiari 4 malformation, precentral convolution, Development Disorders, deformities, Cerebella, HERV-T_19q13.11 provirus ancestral Env polyprotein, predicted, Transmembrane protein, Psychosocial Mental Retardations, Imagings, l(1)G0108, MDDGA6, mKIAA0609, Zeugmatography, Genetic Materials, FLOWERING TIME CONTROL PROTEIN FCA ALPHA, KIAA0609, Filiation, Scan, acetylglucosaminyltransferase-like 1A, Genetic Material, Interhemispheric Commissures, Intellectual Development Disorders, fg, atresia, Congenital cerebellar hypoplasia, beta-tub, Steady-State Free Precession MRI, gyltl1b, Parencephalons, positional polypeptide feature, Beta <eudicots>, nucleus reticulatus (thalami), Disability, mdc1d, malformations, FCAALL.331, INSDC_feature:gene, CARMQ1, Chemical Shift, beta56D, ERV3 envelope protein, DmelCG9277, ERV-3 envelope protein, LARGE_HUMAN, beta1-tub, beta(-), Activities, DTB2, Life Cycles, Phenotypes, gyrus centralis anterior, MDC1D, Spin Echo Imaging, disease, beta-Tub, HERV-R_7q21.2 provirus ancestral Env polyprotein, nucleus thalamicus reticularis, parencephalon, Cerebellums, enr, Chromosome, Patient, Material, cerebellar hypoplasia/atrophy, anomalies, i6, DL4180C, Development Disorder, Cistron, Magnetic resonance imaging, nuclei reticulares (thalami), reticular nucleus thalamus (Arnold), beta-Tub56D, Mental Retardations, Intellectual Development, gyrus praecentralis, humans, betaTub, Specbeta, beta1-Tubulin, Mental, other disease, Neocortical Commissures, Family Member, region or site annotation, Image, MRI Scan, Deficiencies, e(-), CHRMQ1, Gene, antibiotic A 7, Network, electron, LARGE1, Locomotor, Spin Echo Imagings, froggy, Gyltl1a, Human, Homo sapiens, Missense Mutation, B-spec, PPP1R166, betaspec, Functional, fMRI, disease or disorder, Purkinje cell layer, Steady State Free Precession MRI, defects, Man, Callosums, ERV3-1 envelope protein, positional, Echo Imagings, MRI, Mental Retardation, betatub(56D), Genetic, Research, MDDGB6, Hypoplastic cerebellum, Corpus, Magnetic Resonance Image, Elektron, beta[[1]] tubulin, Low intelligence, beta1t, VLDLRCH, Magnetic Resonance, humans., LARGE, Magnetization Transfer Contrast Imaging, Locomotor Activity, NMR Tomography, non-neoplastic, anon-EST:fe1B3, BPFD#36, INSDC_feature:misc_feature, wild turkey, Callosum, cerebellar Purkinje cell layer, SPEC8, Clients, Disorder, HERV-R envelope protein, cerebellar hypoplasia, disorder, Kinship Networks, CG5870, isolated cerebellar agenesis, Shift Imaging, anterior central gyrus, Gaits, Hypoplasia of cerebellum, Family, epilepsy, beta-tubulin56D, Spec-beta, Dmbeta1, Commissures, cerebellum Purkinje layer, Family Research, MRIs, Mental Deficiencies, NMR Imaging, disorders, Idiocy, Tubulin, MR Tomography, Functional Magnetic Resonance Imaging, medical condition, i168, Surface protein, Cistrons, Client, Magnetic Resonance Images, AW047288, Psychosocial Mental, Family Members, development, prophase chromosome, MR, common turkey, Psychosocial Mental Retardation, Chemical Shift Imaging, A-7, agenesis, Shift Imagings, sequence, condition, betaSpec, Neocortical, rare (European definition), Scans, b-Spec, Atrophies, Postures, DmelCG5870, l(1)G0074, l(1)G0198, CAMRQ2, negatron, Corpus Cerebelli, beta[[1]]-tubulin, Locomotor Activities, interphase chromosome, Proton Spin, postnatal growth, prerolandic gyrus, Magnetic, b spectrin, beta1, and global developmental delay, subtotal absence of cerebellum, primary structure of sequence macromolecule, beta, Tub, Psychosocial, AA408956, Deficiency, Interhemispheric Commissure, Mental Deficiency, like-glycosyltransferase, Commissure, cerebellum Purkinje cell layer, beta-spec, Families, Proton Spin Tomography, Modern Man, birth defects, BETA, Turkiye, Spin Echo, growth, Relatives, Corpus Callosums, congenital cerebellar Hypoplasia, Interhemispheric, Spec, glycosyltransferase-like protein LARGE1falseBilMBG Data Access CommitteeData Access Committee EGAC01000000008EGAC01000000008960621885617EGAS00000000099EGAD00010000130