Expanding the DARS phenotype: late-adult onset myelopathy and leukoencephalopathy

A significant proportion of adult-onset neurological disorders remain diagnostic odysseys despite extensive evaluation. Hypomyelination with Brainstem and Spinal Cord Involvement and Leg Spasticity (HBSL) is an autosomal recessive disorder caused by mutations in the cytoplasmic aspartyl-tRNA synthetase (DARS) gene involved in mRNA translation. Clinical features of patients with DARS mutations include developmental delay, leg spasticity, cerebellar dysfunction, cognitive impairment and epilepsy. Most reported cases have been infantile-onset with severe neurological disability and neuroimaging abnormalities. To our knowledge, late-or adult-onset cases have never been reported in the literature. Here, we report for the first time, with video documentation and six-year clinical follow-up, an ethnic Malay patient with onset of spasticity and ataxia in late-adulthood, carrying a pathogenic DARS mutation discovered via whole-genome sequencing. His clinical and radiological findings were consistent with HBSL, but this diagnosis was not considered as, up until now, HBSL has only been reported with childhood/adolescent-onset. This case highlights that HBSL/DARS mutations should now be considered in the differential diagnosis of adult-onset spastic paraplegia and/or leukoencephalopathy.National Research Foundation (NRF)Published versionThis study was funded by Singapore’s SingHealth Foundation (SHF) Institute of Precision Medicine (PRISM) Research Grant (SHF/PRISM008/2016), Singapore’s National Research Foundation (NRF) Fellowship (NRF-NRFF2016-03), and the University of Malaya Parkinson’s Disease and Movement Disorder Research Program (PV035-2017)

Incidentalome from Genomic Sequencing: A Barrier to Personalized Medicine?

Background: In Western cohorts, the prevalence of incidental findings (IFs) or incidentalome, referring to variants in genes that are unrelated to the patient's primary condition, is between 0.86% and 8.8%. However, data on prevalence and type of IFs in Asian population is lacking. Methods: In 2 cohorts of individuals with genomic sequencing performed in Singapore (total n = 377), we extracted and annotated variants in the 56 ACMG-recommended genes and filtered these variants based on the level of pathogenicity. We then analyzed the precise distribution of IFs, class of genes, related medical conditions, and potential clinical impact. Results: We found a total of 41,607 variants in the 56 genes in our cohort of 377 individuals. After filtering for rare and coding variants, we identified 14 potential variants. After reviewing primary literature, only 4 out of the 14 variants were classified to be pathogenic, while an additional two variants were classified as likely pathogenic. Overall, the cumulative prevalence of IFs (pathogenic and likely pathogenic variants) in our cohort was 1.6%. Conclusion: The cumulative prevalence of IFs through genomic sequencing is low and the incidentalome may not be a significant barrier to implementation of genomics for personalized medicine

Family history assessment significantly enhances delivery of precision medicine in the genomics era

10.1186/s13073-020-00819-1Genome Medicine131

Analysis of clinically relevant variants from ancestrally diverse Asian genomes.

10.1038/s41467-022-34116-9Nat Commun1316694

Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production.

Funder: DH | NIHR | Efficacy and Mechanism Evaluation Programme (NIHR Efficacy and Mechanism Evaluation Programme); doi: https://doi.org/10.13039/501100001922Funder: British Heart Foundation (BHF); doi: https://doi.org/10.13039/501100000274Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: Royal Society-Newton Advanced Research Fellow (NA170257/FF-2018-033Funder: Japan Society for the Promotion of Science KAKENHI grants 17K08680Funder: DH | NIHR | Health Services Research Programme (NIHR Health Services Research Programme); doi: https://doi.org/10.13039/501100001923Funder: NIHR Translational ResearchFunder: Biomedical Research Council, SingaporeFunder: the European Research Council under the European Union’s Horizon 2020 research and innovation program. Grant agreement No. 694913Funder: Japan Society for the Promotion of Science KAKENHI grants. Grant ref no. 18K07414Funder: European Research Council under the European Union’s Horizon 2020 research and innovation program. Grant agreement No. 633983Funder: Japan Society for the Promotion of Science KAKENHI grants. Grant ref. 18K07049 and 15K15113 Ministry of Education, Culture, Sports, Science and Technology-Supported Program for the Strategic Research Foundation at Private Universities 2015-19Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production

Analysis of clinically relevant variants from ancestrally diverse Asian genomes

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.</p

Large-Scale Whole-Genome Sequencing of Three Diverse Asian Populations in Singapore

Because of Singapore's unique history of immigration, whole-genome sequence analysis of 4,810 Singaporeans provides a snapshot of the genetic diversity across East, Southeast, and South Asia.</p