Recurrent high‑grade glioma (HGG)-including glioblastoma-remains lethal, with median survival of approximately 6-10 months after first progression, although patients with IDH mutant tumors often have better survival. Recent ASCO/SNO data and expanding trial data are reshaping available treatment strategies. We review evidence for alkylators and anti‑angiogenic therapy; summarize targeted options for rare, actionable alterations; review immuno‑oncology combinations and cellular therapies; highlight DNA damage response (DDR)/radiosensitization strategies and discuss advances in blood-brain barrier modulation and locoregional delivery. We propose a patient‑centered algorithm that prioritizes trial enrollment, biomarker‑guided approaches, steroid stewardship, and quality of life. Lomustine, temozolomide rechallenge, and bevacizumab remain commonly used but provide modest benefit. Targeted agents show meaningful activity only in select subsets (BRAF V600E, NTRK). DDR-directed agents such as ATM/ATR inhibitors show early promise. Immunotherapy advances center on rationale combinations, oncolytic viruses, and locoregionally delivered CAR-T/TCR platforms. Blood-Brain-Barrier (BBB) modulation strategies and adaptive trials are broadening access to innovative therapies. The 2025 landscape features meaningful, if incremental, options-alongside the first ever FDA‑approved therapy for H3K27M‑mutant diffuse midline glioma at relapse-and a pipeline of rational combinatorial approaches poised to refine outcomes for selected patients. This article concentrates on medical options and intentionally omits extended discussions of surgery and radiation beyond their integration with systemic therapies at recurrence. Despite poor overall outcomes, incremental progress across targeted, immune, and delivery-based approaches supports a patient centered strategy emphasizing clinical-trial enrollment, molecular profiling and symptom focused care.
Prosody perception is an often overlooked aspect of human language despite its importance in facilitating spoken language comprehension. Sensitivity to prosodic cues varies between individuals, and prosody perception skills are shown to be associated with various language- and reading-related outcomes. Despite the importance of prosody perception in human communication, its underlying biology is poorly understood. This study investigates the genetic architecture of prosody (speech rhythm) perception and explores its evolutionary roots. We conducted a GWAS of prosody (n = 1,501) as measured by scores on the Test of Prosody via Syllable Emphasis ("TOPsy"). GWAS results yielded 14 suggestive significant signals (p < 5.00 × 10-6). Gene set enrichment analysis identified shared genetic architecture between human prosody perception and key vocal learning brain regions in songbirds, suggesting that human prosody perception may have evolutionary convergence in communication mechanisms in animal vocal learning. Additionally, cross-trait polygenic score analyses suggest shared genetic influences between prosody perception and both word reading and musical beat synchronization, emphasizing how genetics influence prosody perception and its associations with communication-, education-, and music-related traits. These initial efforts could inform advances in communication sciences and disorders as well as educational contexts.
Heterotaxy (HTX) is a congenital disorder characterized by abnormal left-right organ placement, often leading to severe congenital heart disease (CHD). Despite advances in sequencing, many CHD and HTX-associated genes remain functionally unvalidated, hindering effective clinical diagnosis and management. Here, we leveraged a high-throughput CRISPR-Cas9 screening approach in the Xenopus model to rapidly evaluate candidate genes identified from whole-exome sequencing of human CHD patients. Our screen identified Filamin B (FLNB), an actin-binding protein previously linked to skeletal disorders but not to ciliopathies or CHD. We identified 5 probands with CHD and HTX, 3 with recessive and 2 with damaging heterozygous variants in FLNB. Disrupting flnb in Xenopus reproduced key features of the human HTX phenotype, including defects in cardiac development and impaired motile cilia function. Rescue experiments confirmed the functional conservation of human FLNB, directly implicating actin cytoskeletal disruption in ciliogenesis and left-right patterning defects. Our results provide crucial evidence linking human FLNB dysfunction to ciliopathies and CHD and HTX.
Most complex trait association signals reside in the noncoding genome, where defining function is challenging. MPRAs (massively parallel reporter assays) offer a scalable means to test variants' regulatory impacts but are typically cell-type agnostic, pairing cloned fragments with generic "housekeeping" promoters. To explore MPRAs' context sensitivity, we screened a panel of nearly 12,000 fragments across >300 diabetes- and metabolic-trait-associated regions in a pancreatic β cell line model. We compared activity when fragments were placed up- versus downstream of a reporter gene and combined with the synthetic housekeeping promoter super core promoter 1 (SCP1) versus the physiologically relevant human insulin (INS) gene promoter. We identified clear effects of MPRA construct design on regulatory activity. A subset of fragments (n = 702/11,656) displayed positional bias, evenly distributed across up- and downstream preferences. Promoter choice also influenced MPRA activity (n = 698/11,656), mostly biased toward the cell-specific INS promoter (73.4%). A screen for sequence annotations associated with INS promoter preference revealed enrichment for HNF1 binding motifs. HNF1 family transcription factors are key regulators of glucose metabolism disrupted in maturity-onset diabetes of the young (MODY), suggesting genetic convergence between rare coding variants that cause MODY and common type 2 diabetes (T2D)-associated regulatory regions. A follow-up HNF1-focused MPRA highlighted several instances where motif deletion or mutation disrupted regulatory activity specifically in the context of the INS1 promoter and in the β cell model but not in another diabetes-relevant cell type, skeletal muscle. These results identify technical factors that may require careful consideration while designing MPRA experiments.
Keratinizing desquamative squamous metaplasia (KDSM) of the urinary tract is typically a sporadic condition with unclear etiology and treatment options. It is characterized by either a focal or widespread transition of normal urothelium of the bladder and ureters to a stratified squamous keratinizing epithelium. Four individuals from three generations of a single family were ascertained with a likely autosomal dominant form of syndromic KDSM. Whole-genome sequencing was performed on three affected individuals and a truncating variant (RARG NM_000966.6:c.1237C>T; NP_000957.1:p.Arg413∗) in the gene encoding retinoic acid receptor gamma (RARγ) was identified to be segregating with the phenotype. The truncating variant does not destabilize the transcript or protein produced from this allele but instead predicts the loss of half of helix 12 of RARγ, leading to reduced responsiveness of the receptor to all-trans retinoic acid via a dominant-negative mechanism. Mice heterozygous for the variant demonstrated upregulation of cytokeratin-10 in the bladder and ureteric epithelium consistent with keratinizing squamous metaplasia of the urothelium. The implicated dominant-negative mechanism reduces retinoic acid signaling via heterodimeric receptors that incorporate the variant γ subunit and indicates that this condition may be addressable with high-dose retinoic acid receptor agonists.
Unsupervised genome-wide ancestry estimation in unrelated individuals has been a staple in population and medical genetics for decades, and its importance continues to grow with the increasing number of large genetic cohorts of mixed ancestries. We propose an extension to the hapla framework that scales model-based ancestry estimation to unprecedented sample sizes by leveraging inferred haplotype clusters from phased genotype data. Our haplotype cluster-based approach is approximately 5× and 20× faster than the fastest model-free and model-based SNP-based approaches, respectively, for unsupervised genome-wide ancestry estimation on the harmonized Human Genome Diversity Project and 1000 Genomes Project dataset. Furthermore, we demonstrate that it is the most accurate method to date in an extensive simulation study, across a range of sample sizes from thousands to hundreds of thousands of individuals. Our accurate ancestry estimates can help reduce health disparities and accelerate precision medicine efforts in the growing number of biobanks globally.
Chromatin regulation is critical for neurodevelopment, and its disruption has emerged as a key pathogenic mechanism in neurodevelopmental disease, including autism spectrum disorder (ASD), a condition known for genetic and phenotypic heterogeneity. We previously identified an ASD gene, KDM5A, encoding a histone H3 lysine 4 demethylase, and reported de novo and inherited variants in nine individuals with severe ASD and other neurodevelopmental phenotypes. Here, we expand the genetic and phenotypic spectrum of KDM5A-related neurodevelopmental disorders and investigate the functional impact of identified variants. Through international collaborations, we assembled a cohort of 24 additional individuals from 21 families with rare, protein-altering KDM5A variants. All individuals presented with severe speech impairment and intellectual disability, often alongside ASD and other neurodevelopmental features. The variants include missense, nonsense, frameshift, and splice site, distributed across nearly all functional domains of the protein. Structural modeling revealed localized conformational disruptions, particularly at conserved residues in enzymatic or chromatin-interacting domains. For a subset of variants, we demonstrated reduced KDM5A protein levels in cell lines derived from affected individuals. Transcriptomic profiling revealed variant-specific gene expression changes, most pronounced in variants affecting the PLU1 chromatin-binding motif and the Jumonji C domain of the enzymatic core. American College of Medical Genetics and Genomics-guided reclassification supported pathogenicity for the majority of variants, including multiple upgrades from uncertain significance to pathogenic or likely pathogenic. Together, these findings implicate diverse KDM5A alleles in a rare but recurrent form of ASD and establish KDM5A as a key regulator of neurodevelopment and chromatin-mediated ASD pathogenesis.
Dilated cardiomyopathy (DCM) results from systolic dysfunction, while restrictive cardiomyopathy (RCM) is due to diastolic dysfunction. The diverse pathophysiology of primary DCM and RCM suggests distinct underlying genetic mechanisms. A well-established disease gene for DCM and RCM is cardiac troponin I3 (TNNI3), which causes dominant and recessively inherited forms. In children, bi-allelic truncating TNNI3 variants have typically been associated with DCM, and heterozygous missense TNNI3 variants are associated with RCM. We report a 2-year-old female with severe RCM that is genetically caused by a homozygous TNNI3 nonsense variant, c.406C>T (p.Arg136∗), which results in a more distal (C-terminal) truncation than most previously reported disease-associated nonsense variants. In myocardial biopsies of the patient, TNNI3 protein abundance was diminished, suggesting that residual TNNI3 function may underlie RCM, while TNNI3 absence causes DCM. The RCM in this patient was treatment refractory and resulted in a heart transplant at the age of 28 months. Overall, recessive TNNI3 protein truncation causes severe pediatric RCM, suggesting that the allelic status, type of genetic alteration, and length of TNNI3 protein truncation determine cardiomyopathy onset and subtype manifestation.
Index trait bias (also called index event bias) can occur in genetic studies due to conditioning on incident trait, which can bias genetic associations with subsequent traits. We propose the use of two Bayesian Mendelian randomization (MR) methods (Bayesian weighted MR [BWMR] and MR-HORSE) to correct index trait bias in genome-wide association studies (GWASs) of subsequent traits. We compare these Bayesian MR methods to previously proposed methods for index trait bias through a simulation study. We observe that BWMR has similar type I error compared to using an inverse variance weighted MR, weighted median MR, and Dudbridge but has an inflated type I error compared to SlopeHunter. MR-HORSE and SlopeHunter have similar type I errors for smaller correlations between incident and subsequent traits; however, MR-HORSE and SlopeHunter have better controlled type I error for a large negative correlation and large positive correlation, respectively. All methods have comparable power across correlations between incident and subsequent traits. We applied the methods to a GWAS of subsequent acute ischemic stroke (AIS) or 3-point major adverse cardiovascular event after an incident AIS event in the Million Veteran Program and for fasting insulin adjusted for body mass index, and we observed slight differences in the results between the correction methods. We observed that a single index trait bias correction method is not optimal across all scenarios; therefore, applying multiple methods and checking for consistency between the estimates could provide an approach to determine the presence of and correction for index trait bias.
Oxidative stress has been implicated in Parkinson disease (PD). Genes involved in PD, such as PRKN, PINK1, and PARK7, contribute to oxidative stress in dopaminergic neurons. The X-linked G6PD gene encodes glucose 6-phosphate dehydrogenase, an important regulator of oxidative stress. Recent studies suggested that alpha-synuclein aggregates may impair G6PD activity and contribute to dopaminergic neuron loss, and that G6PD mutations may independently increase the risk of PD. In this study, we aimed to examine the role of common and rare G6PD variants in PD across 6 cohorts, including 8,905 PD cases, 16,770 proxy cases, and 394,098 controls. These cohorts were analyzed after stratification by sex and then combined to account for the G6PD X-linked location. Using logistic regression, we did not identify significant associations for common variants in any of the cohorts. The optimized sequence Kernel association (SKAT-O) test was performed to assess the effect of rare variants (minor allele frequency <0.01) across six cohorts, followed by a meta-analysis using metaSKAT, also demonstrating lack of association. In conclusion, we did not find evidence for a role for G6PD in PD.
Autosomal dominant (AD) pathogenic/likely pathogenic (P/LP) variants in Von-Hippel Lindau (VHL) gene cause VHL disease. We characterize VHL variants and disease phenotypes in Black/African American (AA) patients, a demographic not as thoroughly studied. Black/AA patients undergoing germline genetic testing at a CLIA certified commercial laboratory from November 2014 to March 2022 and carrying a P/LP AD VHL gene variant were identified. Personal and family histories were obtained from test requisition forms, and patients were categorized into VHL disease subtypes: Type 1, Type 2A, Type 2B, and Type 2C. Patients with a personal or family history of cancer but no lesions typical of VHL disease were categorized as "Unclassified". Patients with an incomplete personal or family history available were noted as "Unknown". Final analysis included 38 patients. Among the cohort's personal cancer history, hemangioblastoma and pheochromocytoma were most prevalent (16%). Among the cohort's family cancer history, renal cell carcinoma was most prevalent (8%). Type 1 was the most common VHL disease class recorded (34%). Substitution variants were most common (76%); p.Arg167Trp was the most common substitution (8%). Unique variants in Black/AA patients include p.Pro81Leu, p.Leu129Pro, p.Asp121Val, P.His110Profs*49, p.Arg82His. This dataset informs future research on VHL disease and treatment in Black/AA populations.
National guidelines from the US Preventive Services Task Force and the National Comprehensive Cancer Network recommend the use of family-health-history (FHH)-based risk assessment tools to guide genetic testing (GT) among women with an increased risk of inherited cancer and inform personalized cancer risk management. Prior research has focused on attitudes toward and decisions about initial uptake of GT in Black patients but little is known about the factors that impact the subsequent completion of GT after they have already provided consent. Using a community-based participatory research (CBPR) approach, we aimed to identify barriers and actionable strategies to improve GT completion offered through the Breast Health Assessment (BHA), an FHH screening tool administered at routine mammography visits. We conducted semi-structured interviews with 12 Black women who screened high-risk for inherited breast cancer and consented to GT through the BHA, but did not complete saliva sample collection. Thematic analysis revealed that lack of dedicated support throughout the BHA workflow emerged as a key obstacle to sample collection, whereas medical mistrust, shame, and limited knowledge were largely regarded as cultural barriers that had no impact on GT completion. Low utilization among participants reflected logistical challenges highlighting the need to evaluate multi-level implementation processes to better understand and address inequities in GT completion. Participants suggested implementing early educational outreach, culturally relevant messaging, and interpersonal touchpoints to promote GT uptake. By applying a CBPR approach, we translated these findings into actionable, equity-focused strategies to improve GT completion within a population genetic screening program.
Approximately 200 genes have been identified as causative in hereditary hearing loss. Genetic testing is increasingly important, not only for accurate diagnosis but also for predicting audiometric profiles, prognoses, and potential syndromic features. Hereditary hearing loss can be syndromic or nonsyndromic, with nonsyndromic forms further classified by inheritance: autosomal-dominant or autosomal-recessive. In autosomal-dominant cases, three pathological mechanisms-haploinsufficiency, dominant-negative effects, and gain of function-are often implicated. Moreover, specific genes correlate with distinct audiometric patterns: WFS1 variants typically cause low-frequency hearing loss, whereas KCNQ4 and POU4F3 variants are linked to high-frequency loss. To investigate the underlying mechanisms of these frequency-dependent patterns, gene expression across cochlear turns was compared in mice, but interpretations of the results were limited because of inherent structural differences between rodent and primate cochleae. Therefore, the common marmoset (Callithrix jacchus), which offers closer anatomical and functional similarity to human cochleae, was utilized herein as an improved model. Using RNA sequencing (RNA-seq) across cochlear turns of common marmosets, the present study aimed to uncover gene expression and alternative splicing patterns that may explain tonotopic manifestations in hereditary hearing loss, including those caused by WFS1 variants, the present study being one such using common marmoset cochlear RNA-seq data, and these findings are highly valuable for genetic diagnosis and the development of gene therapies.
Single-nucleotide variants (SNVs) and small insertions or deletions (indels) underlie most rare monogenic disorders, yet therapeutic strategies to precisely correct these mutations remain limited. Prime editing enables the repair of such pathogenic variants without introducing double-stranded breaks. Here, we applied CRISPR prime editing to model and correct a de novo GDF11 nonsense mutation (Tyr336∗) identified in a participant from the Undiagnosed Diseases Network with growth delay and multisystem abnormalities. Using HEK293T cells, we generated heterozygous (HET) GDF11 Tyr336∗ clones, which exhibited reduced GDF11 protein levels due to post-translational degradation likely mediated by endoplasmic reticulum- and Golgi-associated quality control pathways. These cells displayed marked Golgi abnormalities, including an increased number of compact, irregularly shaped Golgi structures, findings consistent with Golgi fragmentation and stress. Transcriptomic profiling of HET cells revealed a broad dysregulation of gene networks, including downregulation of metabolic and Golgi-linked biosynthetic genes, and upregulation of cell-adhesion and extracellular matrix genes. These transcriptional shifts paralleled the participant's developmental, neural, and cardiovascular phenotypes. To correct the mutation, we tested multiple bespoke prime editing strategies and identified PE7, in combination with a prime editing guide RNA designed by Pridict, as the most effective ribonucleoprotein complex for rescue. Editing efficiency was further enhanced by introducing an additional silent protospacer-adjacent motif-disrupting mutation, likely preventing both Cas9 re-binding and mismatch repair. Together, these findings support a haploinsufficiency mechanism for the GDF11 Tyr336∗ allele and establish a generalizable framework for disease modeling and allele-specific correction of pathogenic variants in human cells.
Inherited retinal diseases (IRDs) comprise a diverse group of disorders that frequently lead to progressive vision impairment and blindness. Despite advances in genetic testing, a significant number of IRD cases remain genetically unsolved, often due to unidentified disease-associated genes or variants. This study reports additional cases for the newly discovered IRD genes of the AP-5 complex. A comprehensive ophthalmological evaluation was performed for all patients, including retinal imaging (multimodal imaging), visual field testing, and electroretinogram (ERG) testing. Whole-genome and -exome sequencing (WGS and WES) were performed for clinically unsolved IRD patients, and data were analyzed to identify underlying causal variants. The identified variants were subsequently validated using Sanger sequencing. Five unrelated patients from Europe and Iran were identified with a distinctive macular degeneration associated with bi-allelic variants in AP5Z1 (HGNC: 22197) and AP5B1 (HGNC: 25104), subunits of the vesicular fifth adaptor protein (AP-5) complex. The AP-5 complex is the part of the intracellular trafficking machinery thought to be involved in cellular homeostasis and lysosomal functioning in the retinal pigment epithelium (RPE). The identification of bi-allelic variants in two proteins of the AP-5 complex expand the characterization of AP-5 genes in sustaining and preserving normal macular function.
Sphingolipids are integral components of cell membranes and modulate cell survival, proliferation, and apoptosis. ASAH2 is a brain- and gut-enriched gene encoding the neutral N-acylsphingosine amidohydrolase 2, a poorly characterized member of the human ceramidase family. This enzyme plays a pivotal role in maintaining the sphingolipid homeostasis, which is crucial for neurogenesis and synaptic function in the central and peripheral nervous systems. In fact, a dysregulated sphingolipid metabolism is associated with progressive neurological conditions, including Alzheimer disease and Parkinson disease. Here, we report the identification of biallelic ASAH2 variants in an individual with a neurodevelopmental condition featuring cognitive impairment, neuropathy, ophthalmoplegia, and progressive cerebellar and extraocular muscles atrophy. Through exome sequencing, we identified very rare missense ASAH2 variants, predicted to be deleterious by in silico analyses. Muscle biopsy histopathologic evaluation revealed features suggestive of neuropathic damage. Lipidomic profiling revealed a hyper-accumulation of glucosylceramide in the subject's cells. Then, the functional investigation of the ASAH2 variants in Drosophila showed the production of an unstable protein and consistent loss-of-function neuromotor phenotypes. Our findings support ASAH2 as a candidate gene for a previously uncharacterized neurodevelopmental disorder with neuropathic features and progressive cerebellar atrophy, underscoring the important role of this ceramidase in human nervous systems.
An increased frequency of sporadic autosomal dominant disorders has been observed among children born to older fathers. This paternal age effect is thought to reflect an accumulation of new mutations in the male germ line as DNA replication and cell division continue to occur as men age. Genome-wide sequencing is useful for identifying disease-causing genetic variants in patients with suspected genetic diseases and for determining inheritance or de novo mutation of the variants when done in patient-parent trios. We analyzed paternal ages in 593 families who received trio or quad exome or genome sequencing for suspected genetic disease. The mean age of fathers of children with de novo disease-causing variants (35.09 years) was significantly greater than that of children with inherited disease-causing variants (33.78 years, p = 0.04). The mean age of mothers of children with de novo disease-causing variants (31.86 years) was not significantly greater than that of children with inherited disease-causing variants (30.80 years, p = 0.09). Interestingly, when the de novo disease-causing variants were broken down into subgroups by variant type, both mean paternal age and mean maternal age of children with de novo indel variants (paternal = 36.33 years, maternal = 33.34 years) were significantly higher than in children identified to have de novo single-nucleotide variants (paternal = 34.35 years, p = 0.03; maternal = 31.15 years, p = 0.004). This observation, which may have implications for how indels arise, requires further study.
Mitochondrial disorders show remarkable clinical and genetic heterogeneity, and result from variants in either mitochondrial- or nuclear-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly pathway that imports small cysteine-containing substrates. We report a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Western blot analysis showed decreased levels of CHCHD4 and diminished assembly of complexes I and IV in his fibroblasts. To demonstrate that CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring levels of complex I and IV proteins and the associated assembly defects Proteomic studies pointed to electron transport and complex I biogenesis as the main dysregulated pathways and showed a severe loss of several complex I and IV proteins and/or assembly factors rescued by overexpression of wild-type CHCHD4. CHCHD4 has numerous targets and interacting factors and is involved in the export of iron-sulfur clusters synthesized inside mitochondria. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a cause of dysregulated mitochondrial protein import resulting in a severe neurological condition.
Genetic relatives share long stretches of DNA they co-inherited from a common ancestor in identical-by-descent (IBD) segments. Because children inherit half their parents' genomes, the expected amount of DNA relatives share drops by 12 for each generation that separates them, being 2-d for d-degree relatives. Even so, there is substantial variance in sharing rates so that most distant relatives share zero IBD segments. I characterized IBD segment sharing between relatives by simulating 100,000 pairs for each of first through eighth cousins, including once-removed and half-cousins, while modeling both crossover interference and sex-specific genetic maps. My results show that 98.5% of third cousins share at least one IBD segment, while only 32.7% of fifth cousins and 0.96% of eighth cousins have such sharing. These sharing rates are slightly higher than those that arise from models that ignore the more elaborate crossover features and can be filtered by segment length. The resulting segment count distributions are available with an interactive segment length threshold online.
India is the most populous country globally, yet genetic studies involving Indian individuals remain limited. The Indian population is composed of many founder groups and has a mixed genetic ancestry, including an ancestral component not observed anywhere outside of India. This presents a unique opportunity to uncover novel disease variants and develop tailored medical interventions. To facilitate genetic research in India, a crucial first step is to create a foundational resource that serves as a benchmark for future population studies and methods development. Thus, we constructed the largest and most nationally representative linkage disequilibrium (LD) and genotype imputation reference panels in India to date, using high-coverage whole-genome sequencing data of 2,680 participants from the Longitudinal Aging Study in India-Harmonized Diagnostic Assessment of Dementia (LASI-DAD). As an LD reference panel, LASI-DAD includes 69.5 million variants, representing 170% and 213% increases relative to the 1000 Genomes Project and TOP-LD South Asian panels, respectively. Besides serving as an LD lookup panel, LASI-DAD facilitates various statistical analyses relying on precise LD estimates. In polygenic risk score (PRS) analyses, LASI-DAD improved the PRS predictive performance by 2.1%-35.1% across traits and studies. As an imputation reference panel, LASI-DAD enhanced imputation accuracy, measured by the Pearson correlation between imputed and true genotypes, by 3%-101% (mean 38%) compared with the TOPMed panel and by 3%-73% (mean 27%) compared with the Genome Asia Pilot panel across different allele frequencies. The LASI-DAD reference panel is publicly available to benefit future studies.