Spontaneous coronary artery dissection with leucoencephalopathy associated with thrombospondin Type 1 domain containing 1 gene mutation: a case report.

Background: Spontaneous coronary artery dissection (SCAD) is increasingly diagnosed as one of the infrequent causes of acute coronary syndrome. Almost no cause was identified in half of the cases. Here, we report a rare case of spontaneous coronary artery dissection with leucoencephalopathy (SCADLE) associated with a mutation of the thrombospondin Type 1 domain containing 1 (THSD1) gene. Case summary: A 36-year-old lady who presented with ischaemic type chest pain for 4 h duration and found to have anterior ST elevation myocardial infarction. She was thrombolysed with tenecteplase and had good resolution. Her coronary angiogram revealed a spontaneous dissection in the left anterior descending artery (LAD) with TIMI 3 flow. Intra-vascular ultrasound study confirmed the LAD spiral dissection and intramural haematoma. She has had recurrent transient ischaemic attacks 5 years and 7 years ago, and there was a significant family history of young stroke. Her magnetic resonance imaging (MRI) brain showed peri-ventricular white matter hyper-intensities and lacunar infarcts suggestive of leucoencephalopathy. An association with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) and SCAD was suspected, and exome gene sequencing followed by genetic analysis was performed. It identified a variant c.67°C > G (p. Arg224Gly) in the THSD1 gene with normal NOTCH gene. Discussion: Thrombospondin Type 1 domain containing 1 gene encodes proteins involving in the extra-cellular matrix (ECM). This THSD1 mutation is inherited as an autosomal dominant fashion and associated with arterial dissections (rare), fibromuscular dysplasia, intra-cranial aneurysm, and subarachnoid haemorrhages. Therefore, SCADLE could be a result of arteriopathy secondary to dysfunction of ECM proteins in cerebral and coronary vasculature resulting in neurological manifestations and MRI features like in CADASIL and SCAD.

The burden of hospital admissions for skeletal dysplasias in Sri Lanka: a population-based study.

BACKGROUND: Skeletal dysplasias are a diverse group of rare disorders in the chondro-osseous tissue that can have a significant impact on patient's functionality. The worldwide prevalence of skeletal dysplasias at birth is approximately 1:5000 births. To date, disease burden and trends of skeletal dysplasias in the Sri Lankan population have not been described in any epidemiological study. Our aim was to evaluate the burden and the current trends in hospital admissions for skeletal dysplasias in the Sri Lankan population. A retrospective evaluation of hospital admissions for skeletal dysplasia during 2017-2020 was performed using population-based data from the eIMMR database which covers government hospitals in the entire country. The trends in hospital admissions for skeletal dysplasias by calendar year, age, and types of skeletal dysplasia were described using appropriate summary statistics. RESULTS: Respective crude admission rates of skeletal dysplasias in the years 2017, 2018, 2019 and 2020 were 5.2, 8.1, 8.0, and 6.5 per million population. A female predominance (1.4:1) was noted during the studied period. Of all reported cases the majority (n = 268; 44.2%) were children less than 4 years. Each year, 0-4 years age group represented 40-47% of the total hospital admissions. More than half of the cases were reported from Colombo (28.1%) and Kandy (25.4%) districts combined. 60% of cases were diagnosed as osteogenesis imperfecta (OI). Rising trends were observed in the hospital admissions for osteogenesis imperfecta, achondroplasia and osteopetrosis, while other skeletal dysplasia types collectively showed a relatively stable trend. CONCLUSION: This preliminary study revealed a female predominance of skeletal dysplasias and a relatively high admission rate of osteogenesis imperfecta in the Sri Lankan population. A distinct trend was not visible in the studied years probably due to the impact on hospital services due to COVID- Pandemic. Future research on the healthcare burden on families affected by skeletal dysplasia is required to better understand the overall cost of care and identify therapies that reduce admission rates. This study highlights the value of analysing population-based data on rare diseases to improve healthcare in low-resource countries.

Germline variants of uncertain significance, their frequency, and clinico-pathological features in a cohort of Sri Lankan patients with hereditary breast cancer.

BACKGROUND: Next-Generation Sequencing (NGS)-based testing in cancer patients has led to increased detection of variants of uncertain significance (VUS). VUS are genetic variants whose impact on protein function is unknown. VUS pose a challenge to clinicians and patients due to uncertainty regarding their cancer predisposition risk. Paucity of data exists on the pattern of VUS in under-represented populations. This study describes the frequency of germline VUS and clinico-pathological features in Sri Lankan hereditary breast cancer patients. METHODS: Data of 72 hereditary breast cancer patients who underwent NGS-based testing between January 2015 and December 2021 were maintained prospectively in a database and analyzed retrospectively. Data were subjected to bioinformatics analysis and variants were classified according to international guidelines. RESULTS: Germline variants were detected in 33/72(45.8%) patients, comprising 16(48.5%) pathogenic/likely pathogenic variants and 17(51.5%) VUS. Distribution of VUS in breast cancer predisposing genes were :APC:1(5.8%), ATM:2(11.7%), BRCA1:1(5.8%), BRCA2:5(29.4%), BRIP1:1(5.8%), CDKN2A:1(5.8%), CHEK2:2(11.7%), FANC1:1(5.8%), MET:1(5.8%), STK11:1(5.8%), NF2:1(5.8%). Mean age at cancer diagnosis in patients with VUS was 51.2 years. Most common tumour histopathology was ductal carcinoma 11(78.6%). 50% of tumours in patients having VUS in BRCA1/2 genes were hormone receptor negative. 73.3% patients had family history of breast cancer. CONCLUSIONS: A significant portion of patients had a germline VUS. Highest frequency was in BRCA2 gene. Majority had family history of breast cancer. This highlights the need to undertake functional genomic studies to determine the biological effects of VUS and identify potentially clinically actionable variants that would be useful for decision-making and patient management.

The first genetically authenticated case of Leber hereditary optic neuropathy in Sri Lanka: a case report and review of the literature.

INTRODUCTION: Leber hereditary optic neuropathy is a genetic disease of mitochondrial inheritance characterized by bilateral irreversible vision loss, predominantly affecting males. We report the first genetically authenticated Sri Lankan case of Leber hereditary optic neuropathy, illustrating its characteristic features of male predominance and variable penetrance. CASE PRESENTATION: A 15-year-old previously healthy Sri Lankan boy presented with painless progressive vision loss in his right eye, followed by vision loss in his left eye within 3 months. There was no history of drug or toxin exposure, or a family history of vision loss. His parents were nonconsanguineous. On examination, he could only perceive light. Funduscopy revealed bilateral optic atrophy. Routine hematological and biochemical blood tests, including inflammatory markers, were normal. Cranial magnetic resonance imaging was unremarkable. Optical coherence tomography, and the clinical presentation, suggested a diagnosis of Leber hereditary optic neuropathy, which was confirmed by detection of m.14484T > C pathogenic variant in the MT-ND6 gene through targeted genetic analysis for the three common pathogenic variants in mitochondrial deoxyribonucleic acid. He was homoplasmic for the variant, and his asymptomatic mother and two female siblings were also found to be harboring the variant with homoplasmy. CONCLUSIONS: This case report is intended to increase awareness of Leber hereditary optic neuropathy, and highlights the need to consider this rare diagnosis in the appropriate clinical context. It also illustrates the phenomena of incomplete penetrance and male predominance, and suggests the possibility of an X-linked gene governing Leber hereditary optic neuropathy disease expression, which warrants further investigation.

A comprehensive analysis of chromosomal polymorphic variants on reproductive outcomes after intracytoplasmic sperm injection treatment.

Recent studies suggest that chromosomal polymorphic variations are associated with infertility. A systematic review of chromosomal polymorphisms in assisted reproduction found an association with higher rates of miscarriage. Aim of this study is to analyse the influence of specific types or number of chromosomal polymorphic variations on reproductive outcomes of couples undergoing ICSI treatment. We analysed data from 929 fresh and frozen embryo transfer cycles of 692 women who underwent karyotyping analysis using Giemsa-Trypsin-Leishman (GTL) banding prior to the ICSI procedure at the Fertility Centre of Lanka Hospitals Corporation Plc, Sri Lanka, from January 2016 to December 2018. The outcomes of interest were the pregnancy, miscarriage and live birth rate per cycle. There was no evidence of a difference in the reproductive outcomes between carriers or non-carriers of any type or number of chromosomal polymorphic variation. Our data, in contrast to previous studies, does not support a deleterious effect for the type or number of chromosomal polymorphic variations on reproductive outcomes. However, additional prospective, adequately powered studies, conducted in multiethnic populations, are required to further investigate whether the detection of chromosomal polymorphic variants prior to assisted conception may in fact be a futile diagnostic tool.

A recurrent homozygous missense DPM3 variant leads to muscle and brain disease.

Biallelic pathogenic variants in the genes encoding the dolichol-phosphate mannose synthase subunits (DPM) which produce mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation, are rare causes of congenital disorders of glycosylation. Pathogenic variants in DPM1 and DPM2 are associated with muscle-eye-brain (MEB) disease, whereas DPM3 variants have mostly been reported in patients with isolated muscle disease-dystroglycanopathy. Thus far, only one affected individual with compound heterozygous DPM3 variants presenting with myopathy, mild intellectual disability, seizures, and nonspecific white matter abnormalities (WMA) around the lateral ventricles has been described. Here we present five affected individuals from four unrelated families with global developmental delay/intellectual disability ranging from mild to severe, microcephaly, seizures, WMA, muscle weakness and variable cardiomyopathy. Exome sequencing of the probands revealed an ultra-rare homozygous pathogenic missense DPM3 variant NM_018973.4:c.221A>G, p.(Tyr74Cys) which segregated with the phenotype in all families. Haplotype analysis indicated that the variant arose independently in three families. Functional analysis did not reveal any alteration in the N-glycosylation pathway caused by the variant; however, this does not exclude its pathogenicity in the function of the DPM complex and related cellular pathways. This report provides supporting evidence that, besides DPM1 and DPM2, defects in DPM3 can also lead to a muscle and brain phenotype.

Genome-wide linkage search for cancer susceptibility loci in a cohort of non BRCA1/2 families in Sri Lanka.

OBJECTIVE: Although linkage studies have been utilized for the identification of variants associated with cancer in the world, little is known about their role in non BRCA1/2 individuals in the Sri Lankans. Hence we performed linkage analysis to identify susceptibility loci related to the inherited risk of cancer in a cohort of Sri Lankans affected with hereditary breast cancer. The Illumina global screening array having 654,027 single nucleotide polymorphism markers was performed in four families, in which at least three individuals within third degree relatives were affected by breast cancer. Two-point parametric linkage analysis was conducted assuming disease allele frequency of 1%. Penetrance was set at 90% for carriers with a 10% phenocopy rate. RESULTS: Thirty-one variants exhibited genome-wide suggestive HLODs. The top overall HLOD score was at rs1856277, an intronic variant in MYO16 on chromosome 13. The two most informative families also suggested several candidate linked loci in genes, including ERAP1, RPRM, WWOX, CDH1, EXOC1, HUS1B, STIM1 and TUSC1. This study provides the first step in identifying germline variants that may be involved in risk of cancer in cancer-aggregated non-BRCA1/2 families from the understudied Sri Lankan population. Several candidate linked regions showed suggestive evidence of linkage to cancer risk.

Assessment of iron overload in a cohort of Sri Lankan patients with transfusion dependent beta thalassaemia and its correlation with pathogenic variants in HBB, HFE, SLC40A1, and TFR2 genes.

BACKGROUND: Iron overload (IO) is a complication in transfusion dependent beta thalassaemia (TDT). Pathogenic variants in genes involving iron metabolism may confer increased risk of IO. The objective of this study was to determine the magnitude of the cardiac and hepatic IO and determine whether pathogenic variants in HFE, SLC40A1 and TFR2 genes increase the risk of IO in a cohort of TDT patients in Sri Lanka. MATERIALS AND METHODS: Fifty-seven (57) patients with TDT were recruited for this study. Serum ferritin was done once in 3 months for a period of one year in all. Those who were ≥ 8 years of age (40 patients) underwent T2* MRI of the liver and heart. Fifty-two (52) patients underwent next generation sequencing (NGS) to identify pathogenic variants in HBB, HFE, SLC40A1 and TFR2 genes. RESULTS: The median age of the patients of this cohort was 10 years. It comprised of 30 (52.6%) boys and 27 (47.4%) girls. The median level of serum ferritin was 2452 ng/dl. Hepatic IO was seen in 37 (92.5%) patients and cardiac IO was seen in 17 (42.5%) patients. There was no statistically significant correlation between serum ferritin and hepatic or cardiac IO. Thirty-two (61.5%), 18 (34.6%), 2 (3.8%) of patients were homozygotes, compound heterozygotes and heterozygotes for pathogenic variants in the HBB gene. Eight (15.4%) and 1 (1.9%) patients were heterozygotes for pathogenic and likely pathogenic variants of HFE genes respectively. There were no pathogenic variants for the TfR2 and SLC40A1 genes. The heterozygotes of the pathogenic variants of the HFE were not at increased risk of IO. CONCLUSIONS: Cardiac T2* MRI helps to detect cardiac IO in asymptomatic patients. It is important to perform hepatic and cardiac T2* MRI to detect IO in patients with TDT. There was no statistically significant correlation between pathogenic variants of HBB and HFE genes with hepatic and cardiac IO in this cohort of patients.

Modification and Validation of a Maturity Assessment Tool for Public Health Information System Implementations in Sri Lanka.

INTRODUCTION: Maturity models assess the snapshot view of an organization and simultaneously guides the organization to advance on a road map towards ultimate levels of maturity. The health industry has recently embraced maturity models as a tool to improve the management of health information systems. Most electronic health information systems in Sri Lanka need assessment and monitoring and can benefit vastly by adopting maturity models. This study was conducted to modify and adopt a maturity model for public health institutions in Sri Lanka. METHODS: A review of the literature was done to identify a suitable model to measure the maturity of the public health information system implementations. A Modified Delphi study was then carried out with six experts to adapt the selected maturity tool, Public Health Information Technology (PHIT) maturity index, to the Sri Lankan context. Necessary modifications to the PHIT tool were done according to the comments gathered in the Modified Delphi rounds, and the validity of the tool was established. Finally, Key Informant Interviews were carried out with nine interviewees to qualitatively validate the instrument. RESULTS: The Public Health Information Technology maturity index developed by the University of Maryland, USA, was modified to suit the Sri Lankan context. Comments from the experts were accommodated during the initial rounds of the Modified Delphi study. It further derived the following values, indicating excellent content validity: I-CVI > 0.8 for 57 total items, S-CVI/Avg = 0.988, S-CVI/UA = 0.929 and Free-marginal kappa = 0.95. DISCUSSION AND CONCLUSIONS: Modified and validated PHIT tool can be used to measure the maturity of public health institutions in similar contexts.

Genetic determinants of syndactyly: perspectives on pathogenesis and diagnosis.

The formation of the digits is a tightly regulated process. During embryogenesis, disturbance of genetic pathways in limb development could result in syndactyly; a common congenital malformation consisting of webbing in adjacent digits. Currently, there is a paucity of knowledge regarding the exact developmental mechanism leading to this condition. The best studied canonical interactions of Wingless-type-Bone Morphogenic Protein-Fibroblast Growth Factor (WNT-BMP-FGF8), plays a role in the interdigital cell death (ICD) which is thought to be repressed in human syndactyly. Animal studies have displayed other pathways such as the Notch signaling, metalloprotease and non-canonical WNT-Planar cell polarity (PCP), to also contribute to failure of ICD, although less prominence has been given. The current diagnosis is based on a clinical evaluation followed by radiography when indicated, and surgical release of digits at 6 months of age is recommended. This review discusses the interactions repressing ICD in syndactyly, and characterizes genes associated with non-syndromic and selected syndromes involving syndactyly, according to the best studied canonical WNT-BMP-FGF interactions in humans. Additionally, the controversies regarding the current syndactyly classification and the effect of non-coding elements are evaluated, which to our knowledge has not been previously highlighted. The aim of the review is to better understand the developmental process leading to this condition.

Ensuring best practice in genomics education and evaluation: reporting item standards for education and its evaluation in genomics (RISE2 Genomics).

PURPOSE: Widespread, quality genomics education for health professionals is required to create a competent genomic workforce. A lack of standards for reporting genomics education and evaluation limits the evidence base for replication and comparison. We therefore undertook a consensus process to develop a recommended minimum set of information to support consistent reporting of design, development, delivery, and evaluation of genomics education interventions. METHODS: Draft standards were derived from literature (25 items from 21 publications). Thirty-six international experts were purposively recruited for three rounds of a modified Delphi process to reach consensus on relevance, clarity, comprehensiveness, utility, and design. RESULTS: The final standards include 18 items relating to development and delivery of genomics education interventions, 12 relating to evaluation, and 1 on stakeholder engagement. CONCLUSION: These Reporting Item Standards for Education and its Evaluation in Genomics (RISE2 Genomics) are intended to be widely applicable across settings and health professions. Their use by those involved in reporting genomics education interventions and evaluation, as well as adoption by journals and policy makers as the expected standard, will support greater transparency, consistency, and comprehensiveness of reporting. Consequently, the genomics education evidence base will be more robust, enabling high-quality education and evaluation across diverse settings.

A novel variant in the COL6A1 gene causing Ullrich congenital muscular dystrophy in a consanguineous family: a case report.

BACKGROUND: Collagen VI-related dystrophies are a subtype of congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2 or COL6A3 genes affecting skeletal muscles and connective tissue. The clinical phenotype ranges from the milder Bethlem myopathy to the severe Ullrich congenital muscular dystrophy (UCMD). Herein, we report the first consanguineous Sri Lankan family with two children affected with UCMD due to a novel variant in the COL6A1 gene. CASE PRESENTATION: Two sisters, aged 10-years and 7-years, presented with progressive, bilateral proximal muscle weakness. Both probands had delayed motor milestones and demonstrated difficulty in standing from a squatting position, climbing stairs and raising arms above the shoulders. Cognitive, language and social development were age appropriate. Examination showed proximal muscle weakness of the upper and lower extremities and hyperlaxity of the wrist and fingers in both with some variability in clinical severity noted between the two siblings. Serum creatine kinase levels were elevated, and electromyography showed low polyphasic motor unit potentials in the 10-year-old and myopathic features with short duration motor unit potentials with no polyphasia in the 7-year-old. Whole exome sequencing (WES) was performed and a novel, homozygous missense, likely pathogenic variant in exon 25 of COL6A1 gene [NM_001848: c.1667G > T;NP_001839.2:p.Gly556Val] was identified in both probands. This variant was validated by Sanger sequencing in proband 1 as well as proband 2, and the parents and an unaffected sibling were found to be heterozygote carriers for the same variant. CONCLUSIONS: The findings in this family add to the expanding number of COL6A1 variants identified and provides a better understanding of the genotype-phenotype correlations associated with UCMD.

Comparative Analysis of the Genetic Variants in Haematopoietic Stem/Progenitor and Mesenchymal Stem Cell Compartments in de novo Myelodysplastic Syndromes.

Myelodysplastic Syndromes (MDS) are hematological clonal disorders. Bone marrow (BM) mesenchymal stem cells (MSCs) interact with the haematopoietic stem and progenitor cells (HSPCs) to regulate haematopoiesis. We studied the genetic variation profiles of BM derived CD34+ HSPCs and MSCs of same patient in a South Asian de novo MDS cohort with 20 patients. A total of 42 genes (variants 471) and 38 genes (variants 232) were mutated in HSPCs and MSCs respectively and majority (97%) were distinct variants. Variants included both known and novel, with variants predicted as pathogenic. In both cell types, most frequently mutated genes were TET2, KDM6A, BCOR, EZH2 and ASXL. DNA methylation and chromatin remodeling were shown to be affected in both cell types with a high frequency. RNA splicing was affected more in HSPCs. Gene variants in the cohesion complex and epigenetic mechanisms were shown to co-exist. We report variant profile of MSCs and CD34+ HSPCs from a South Asian cohort, with novel variants with potential for further study as biomarkers in MDS. Distinct variants confined to each cellular compartment indicate that the genetic variations occur following lineage commitment.

Frontometaphyseal dysplasia 1 in a patient from Sri Lanka.

A Sri Lankan male child with supraorbital hyperostosis, broad nasal bridge, small mandible, severe kyphoscoliosis, distal joint contractures of the hands and long second and third toes is described. A hemizygous pathogenic variant in exon 22 of the filamin A (FLNA) gene [NM_001110556.1: c.3557C>T; which leads to a nonsynonymous substitution of serine by leucine at codon 1186 in the FLNA protein; NP_001104026.1: p.Ser1186Leu] was identified. The clinical features observed in this patient were consistent with the cardinal manifestations seen in frontometaphyseal dysplasia 1 (FMD1). However, characteristic extra skeletal manifestations such as cardiac defects, uropathy, and hearing impairment which have previously been reported in association with this condition were absent in this patient.

Rubinstein-Taybi syndrome in diverse populations.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.

Functional evaluation of five BRCA2 unclassified variants identified in a Sri Lankan cohort with inherited cancer syndromes using a mouse embryonic stem cell-based assay.

Next-generation sequencing of Sri Lankan families with inherited cancer syndromes resulted in the identification of five BRCA2 variants of unknown clinical significance. Interpreting such variants poses significant challenges for both clinicians and patients. Using a mouse embryonic stem cell-based functional assay, we found I785V, N830D, and K2077N to be functionally indistinguishable from wild-type BRCA2. Specific but mild sensitivity to olaparib and reduction in homologous recombination (HR) efficiency suggest partial loss of function of the A262T variant. This variant is located in the N-terminal DNA binding domain of BRCA2 that can facilitate HR by binding to dsDNA/ssDNA junctions. P3039P is clearly pathogenic because of premature protein truncation caused by exon 23 skipping. These findings highlight the value of mouse embryonic stem cell-based assays for determining the functional significance of variants of unknown clinical significance and provide valuable information regarding risk estimation and genetic counseling of families carrying these BRCA2 variants.

Turner syndrome in diverse populations.

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p < .001) was found for TS versus general population controls and 0.925 (p < .001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome.

A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry. Here we extend comprehensive haplotype analysis of the HD mutation to key populations of Southern European, South Asian, Middle Eastern, and admixed African ancestry. In each of these populations, the HD mutation occurs predominantly on the A2 HTT haplotype. Analysis of HD haplotypes across all affected population groups enables rational selection of candidate target SNPs for development of allele-selective gene silencing therapeutics worldwide. Targeting SNPs on the A1 and A2 haplotypes in parallel is essential to achieve treatment of the most HD-affected subjects in populations where HD is most prevalent. Current allele-specific approaches will leave a majority of individuals with HD untreated in populations where the HD mutation occurs most frequently on the A2 haplotype. We further demonstrate preclinical development of potent and selective ASOs targeting SNPs on the A2 HTT haplotype, representing an allele-specific treatment strategy for these individuals. On the basis of comprehensive haplotype analysis, we show the maximum proportion of HD-affected subjects that may be treated with three or four allele targets in different populations worldwide, informing current allele-specific HTT silencing strategies.