Rare missense TUBGCP5 gene variant in a patient with primary microcephaly |
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| Affiliation: | 1. Institute of Medical Genetics, University of Zurich, Schlieren, Zurich, Switzerland;;2. FRIGE’s Institute of Human Genetics, FRIGE House, Satellite, Ahmedabad, India;;3. Sahyadri Medical Genetics and Tissue Engineering Facility, Kothrud, Pune and Bharati Hospital and Research Center Dhankawadi, Pune, India;;4. Institute of Medical Genetics & Genomics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India;;5. Unità Operativa Complessa di Genetica Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, and Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Rome, Italy;;6. Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA;;7. Department of Neurology, Boston Children’s Hospital, Boston, MA, USA;;8. Service de Neuropédiatrie, Hôpital Universitaire Robert Debré, APHP, Paris, France;;9. Département de Génétique, Hôpital Universitaire Robert Debré, APHP, Paris, France;;10. Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;;11. Division of Pediatric Neurology, University Children’s Hospital Zurich, Zurich, Switzerland;;12. Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria;;13. Child Development Center, University Children’s Hospital Zurich, Zurich, Switzerland;;14. Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland;;15. Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland. |
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| Abstract: | Primary microcephalies (MCPH) are characterized by microcephaly (HC -2 SD at birth) in the absence of visceral malformations. To date, less than 20 genes have been associated with MCHP, several of which are involved in the formation and function of the centrosome.Here, we report a novel missense variant in the TUBGCP5 gene in a patient with primary microcephaly and mild developmental delay. The TUBCGP5 gene (tubulin gamma complex associated protein 5) is a paralog of TUBGCP4 and TUBGCP6, both of which are known MCPH associated genes, and like its’ paralogs, is involved in centrosome formation. Furthermore, the TUBGCP5 gene is located in the 15q11.2 BP1-BP2 microdeletion Burnside-Butler susceptibility locus that is part of the larger Prader-Willi/Angelman region. Common clinical features of the 15q11.2 BP1-BP2 microdeletion include general developmental and neurodevelopmental delay which may occasionally be accompanied by yet unexplained microcephaly.In our patient, the TUBGCP5:c.2180T > G, p.Phe727Cys missense variant was identified in compound heterozygous state with 15q11.2 BP1-BP2 microdeletion using whole exome sequencing, after the initial analyses of known MCPH genes failed to identify a conclusively causative variant. The identified variant is rare and highly conserved, as shown by population allele frequency data from ExAC and GnomAD, as well as comparisons with all other vertebrates. Based on this evidence we suggest that the identified TUBGCP5 variant in our patient may thus represent a novel cause of MCPH with mild developmental delay and may play a role in occurrence of microcephaly in 15q11.2 microdeletion carriers. Further studies are required to further clarify the causality and penetrance of TBGCP5 variants in primary microcephaly. |
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| Keywords: | Primary microcephaly Tubulin gamma complex associated protein 5 Missense variant Mild developmental delay |
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