Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing |
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| Institution: | 1. Department of Molecular Endocrinology, National Center for Child Health and Development, Tokyo, Japan;2. Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan;3. Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;1. Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, India;2. Paediatric Neurology, Dheemahi Child Neurology and Development Center, Shimogga, India;3. Department of Neuroimaging and Interventional Radiology, STAR Institute of Neurosciences, STAR Hospitals, Hyderabad, India;1. Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India;2. Department of Pediatric Orthopaedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India;3. Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium;4. Current affiliation: Center for Human Genetics, University Hospitals Leuven and KU Leuven, Leuven, Belgium;1. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA;2. Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland;3. Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland;4. Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA;1. Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy;2. Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, 80131, Italy;3. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova, Genova, Italy;4. Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada;5. Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, QC, H3A 1B1, Canada;6. Department of Radiology, \"Tortorella\" Private Hospital, Salerno, Italy;7. IRCCS Istituto Giannina Gaslini, Genova, Italy;8. Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy;9. Department of Biotechnology and Applied Sciences, University of L''Aquila, Aquila, Italy;1. Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel;2. Department of Pediatrics & Genetics, Makassed Hospital, Al-Quds Medical School, E. Jerusalem, Palestine;3. Department of Radiology, Hadassah Medical Organization, Jerusalem, Israel;4. Division of Ophthalmology, Hadassah Medical Organization, Jerusalem, Israel;5. Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel |
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| Abstract: | Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016–2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1. |
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| Keywords: | Microcephaly Neurodevelopmental disorders Genetic heterogeneity Exome sequencing |
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