Mosaicism in ASXL3-related syndrome: Description of five patients from three families
| Autor: | Katrina Prescott, Anna Platt, Sumit Punj, Meena Balasubramanian, Deciphering Developmental Disorders Study, Schaida Schirwani, Sahar Mansour, Natalie Hauser, Natalie Canham |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Developmental Disabilities Germline mosaicism Disease 030105 genetics & heredity Saliva sample Biology Germline 03 medical and health sciences Neurodevelopmental disorder Genetics medicine Humans Child Gene Genetics (clinical) Mechanism (biology) Mosaicism General Medicine medicine.disease Pedigree genomic DNA 030104 developmental biology Child Preschool Mutation Female Transcription Factors |
| Zdroj: | European journal of medical genetics. 63(6) |
| ISSN: | 1878-0849 |
| Popis: | De novo pathogenic variants in the additional sex combs-like 3 (ASXL3) gene cause a rare multi-systemic neurodevelopmental disorder. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. There is one previous report of ASXL3-related syndrome caused by de novo pathogenic variants in two siblings suggesting gonadal mosaicism. In this report, we present five patients with ASXL3-related syndrome, describing two families comprising two non-twin siblings harbouring apparent de novo pathogenic variants in ASXL3. Parents were clinically unaffected and there was no evidence of mosaicism from genomic DNA on exome-trio data, suggesting germline mosaicism in one of the parents. We also describe clinical details of a patient with typical features of ASXL3-related syndrome and mosaic de novo pathogenic variant in ASXL3 in 30-35% of both blood and saliva sample on trio-exome sequencing. We expand the known genetic basis of ASXL3-related syndromes and discuss mosaicism as a disease mechanism in five patients from three unrelated families. The findings of this report highlight the importance of taking gonadal mosaicism into consideration when counselling families regarding recurrence risk. We also discuss postzygotic mosaicism as a cause of fully penetrant ASXL3-related syndrome. |
| Databáze: | OpenAIRE |
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