The clinical spectrum and molecular genetics of congenital imprinting disorders in Hong Kong

Abstract

Congenital imprinting disorders (IDs) are a group of rare multi-systemic diseases affecting growth, metabolism and development. They are clinically and epigenetically heterogeneous, and are caused by uniparental disomy, epimutation, dosage change or mutation of imprinted genes. Currently there are more than 100 imprinted genes being identified in human genome and there are 8 classical human congenital IDs. With the advancement in genomic technology, more novel IDs have been discovered and reported in the literature. Despite the advancement, there is relative paucity of study regarding congenital IDs among Hong Kong Chinese. The aim of this thesis is to study the clinical spectrum and molecular genetics of major congenital IDs in Hong Kong at territory-wide basis. In total, 212 cases of different IDs were studied. These included common classical IDs (Prader-Willi Syndrome (PWS), Angelman Syndrome (AS), Beckwith-Wiedemann Syndrome (BWS) and Silver-Russell Syndrome (SRS)) in part II and less common IDs (Temple Syndrome (TS), Kagami-Ogata Syndrome (KOS) and Pseudohypoparathyroidism type 1b (PHP-1b)) in part III of this thesis. Among them, PWS is the most common with the incidence of 1/15,986 in Hong Kong while KOS is the least common with incidence of 1/227,450. The molecular spectrum of these IDs are comparable with those from other populations except there are more upd(15)pat and UBE3A mutation in our Chinese AS. Their phenotype-(epi)genotype correlations are also being studied. Three novel IDs including 15q duplication syndrome, Alveolar capillary dysplasia with misalignment of pulmonary veins (ACPMPV) and Multilocus Imprinting Disturbances (MLID) disorder have been studied in part IV of this thesis. For 15q duplication syndrome, the prevalence in our locality is 1.0% and 2.9% among those patients with intellectual disability and autism spectrum disease respectively. In our first Chinese familial ACPMVP case, we have demonstrated the parent-of-origin imprinting effect on FOXF1 gene. Finally, 25% of KCNQ1OT1:TSS-DMR hypomethylation related BWS and 11.1% of H19/IGF2:IG-DMR hypomethylation related SRS in our cohort have MLID. This prevalence rate is comparable with the results of other studies. Despite no demonstrable difference in clinical phenotype among those MLID and single locus methylation defect related BWS and SRS in our study, we have reported the first Chinese case of coexisting BWS and PHP-1b phenotype in MLID related BWS patient in this thesis. Based on results among our studies, a diagnostic algorithm for suspected congenital ID is proposed in part V of this thesis. The first line investigation currently recommended should be locus specific methylation study like Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) method based on clinical phenotype, then followed by sequencing of related imprinted gene if available. Since somatic mosaicism is common among IDs, testing on other tissue should be pursued to rule out tissue specific mosaicism if the first line testing is negative. However when atypical phenotypes happen, genome wide uniparental disomy or MLID should be considered. To conclude, this thesis is the first comprehensive study of congenital IDs in Hong Kong. The findings are important to understand the epidemiology, clinical manifestations, molecular spectrum and phenotype-(epi)genotype correlation among the major IDs in Hong Kong.