How common is mosaicism? The 9 years-experience in a university affiliated genetic clinic in Hong Kong

Abstract

Background: Mosaicism refers to the co-existence of 2 or more genetically distinct cell populations in an individual. It can be somatic, gonadal or gonosomal. They arise from de novo mutations, which can occur during gametogenesis or postzygotic. It is clinically important as i) de novo mutations are associated with neurodevelopmental disorders, ii) mosaicism affects how the disease expresses, and iii) recurrence risk varies with the type of mosaicism. In this study, we aim to investigate how common mosaicism is in local patients. Method: We perform a retrospective review from 2010 to 2019 on all patients evaluated by the HKU Clinical Genetic team. We provide genetic evaluation and counselling for children but also adult patients in prenatal and preimplantation genetic diagnosis. A total of 2700 patient records have been reviewed to identify genetic mosaicism using various cytogenetic and molecular technologies. Results: We identified evidence of mosaicism in 39 subjects including 6 from prenatal diagnosis. In 3, parental mosaicism is evident while 36 are mosaicism in the patient. Fifteen are identified cytogenetically, including Turner syndrome (n=7), Pallister Killian syndrome (n=2), and 1 each for trisomy 8, trisomy 9, Klinefelter syndrome, Down syndrome, 9p deletion and triple X. The other 24 are molecular causes, including PIK3CA-related overgrowth spectrum (n=13), pigmentary mosaicism (n=2), PIK3CA-related autism (n=2), and 1 each for NF2-associated atypical meningioma, NEMO-associated Incontinentia Pigmenti, PTPN11-associated Juvenile Monomyelocytic leukaemia, UPD 11-assocoiated Beckwith Wiedemann syndrome, EYA1-associated Brachio-Oto-Renal syndrome, CDKL5-associated epilepsy and KRAS-associated Encephalo Craniocutaneous Lipomatosis. Other than these, there are also 3 cases that are clinically suspected but not yet genetically confirmed. Evidence of mosaicism is seen in 1.4% cases (39/2700) we have seen. Conclusions: Recent large cohort studies of neurodevelopmental disorders showed mosaicism is present at 3.5%, 5.1% and 4.2% in epilepsy (PMID:28837158), autism(PMID:27632392) and intellectual disability (ID) (PMID:28867142) respectively. In our cohort, the percentage of mosaicism is 1.4% and is likely underestimated. Detection of mosaicism can be improved by i) lowering the detection threshold in our bioinformatic pipeline, ii) collecting multiple specimens from patients/parents other than blood, and iii) performdigital PCRor high depth NGS using molecular barcoding or molecular inversion probes. Acknowledgment: ACY Lui is a year 3 Bachelor of Medicine and Bachelor of Surgery (MBBS) student in HKU. This work represents part of the coursework for his enrichment year. We would like to thank all the patients and their families for providing invaluable information for this study.