Implementation of Public Funded Genome Sequencing in Evaluation of Fetal Structural Anomalies.

With the advancements in prenatal diagnostics, genome sequencing is now incorporated into clinical use to maximize the diagnostic yield following uninformative conventional tests (karyotype and chromosomal microarray analysis). Hong Kong started publicly funded prenatal genomic sequencing as a sequential test in the investigation of fetal structural anomalies in April 2021. The objective of the study was to evaluate the clinical performance and usefulness of this new service over one year. We established a web-based multidisciplinary team to facilitate case selection among the expert members. We retrospectively analyzed the fetal phenotypes, test results, turnaround time and clinical impact in the first 15 whole exome sequencing and 14 whole genome sequencing. Overall, the molecular diagnostic rate was 37.9% (11/29). De novo autosomal dominant disorders accounted for 72.7% (8/11), inherited autosomal recessive disorders for 18.2% (2/11), and inherited X-linked disorders for 9.1% (1/11). The median turnaround time for ongoing pregnancy was 19.5 days (range, 13-31 days). Our study showed an overall clinical impact of 55.2% (16/29), which influenced reproductive decision-making in four cases, guided perinatal management in two cases and helped future family planning in ten cases. In conclusion, our findings support the important role of genome sequencing services in the prenatal diagnosis of fetal structural anomalies in a population setting. It is important to adopt a multidisciplinary team approach to support the comprehensive genetic service.

Epidemiology and outcomes of pediatric transplant-associated thrombotic microangiopathy in Hong Kong.

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) is an under-recognized yet potentially devastating complication of hematopoietic stem cell transplantation (HSCT) which had increased awareness in recent years. This report summarizes the demographics and outcomes of pediatric TA-TMA in Hong Kong. METHODS: All patients aged below 18 years who underwent HSCT in the Hong Kong Children's Hospital and were diagnosed to have TA-TMA during the 2-year period from April 1, 2019 to March 31, 2021 were included. RESULTS: A total of 73 transplants (51 allogeneic and 22 autologous) in 63 patients had been performed. Six patients (four males and two females) developed TA-TMA at a median duration of 2.5 months post-HSCT. The incidence rate was 9.52%. Of the six TA-TMA patients, five underwent allogenic one underwent autologous HSCT, respectively. Three of them were histologically proven. All four patients with cyclosporine had stopped the drug once TA-TMA was suspected. Median six doses of eculizumab were administered to five out of six patients. Three patients died (two due to fungal infection and one due to acute-on-chronic renal failure) within 3 months upon diagnosis of TA-TMA. Among three survivors, two stabilized with mild stage 2 chronic kidney disease (CKD) while the other suffered from stage 5 end-stage CKD requiring lifelong dialysis. CONCLUSION: In conclusion, recognition and diagnosis of TA-TMA are challenging. Early recognition and prompt administration of complement blockage with eculizumab may be beneficial in selected cases. Further prospective research studies are recommended to improve the management and outcomes of TA-TMA.

Dystroglycanopathy with two novel POMT1 mutations in a Chinese boy with developmental delay and muscular dystrophy.

Alpha-dystroglycanopathies are a group of diseases due to reduced glycosylation of alpha-dystroglycan, which commonly result from mutations in POMT1, POMT2, and POMGnT1. Patients with alpha-dystroglycanopathies present with muscular, cerebral, and ocular involvements with differing severities. We reported a boy who presented with muscular dystrophy, developmental delay, and non-specific white matter lesions. Mutation analysis of POMT1 was performed and revealed two novel mutations, a substitution mutation (c.176T>G) and a duplication mutation (c.2059dupC) which results in premature termination of translation. In-silico prediction in five different platforms concurred that the substitution is damaging, and functional studies by immunofluorescence revealed lack of staining in the carbohydrate moiety of alpha-dystroglycan, confirming the molecular findings in a functional manner. In conclusion, we reported the first case of genetically confirmed alpha-dystroglycanopathy due to mutations in POMT1 in Chinese.