382 results

Large-scale blood pressure GWAS accounting for gene-depression interactions in 564,680 individuals from diverse populations

Songmi Lee; Clint L. Miller; Amy R. Bentley et al.

HGG Advances, Vol. 7 No. 2 · 2026 · English · DOAJ Scopus

Summary: Gene-environment interactions may enhance our understanding of blood pressure (BP) biology. We conducted a meta-analysis of multi-population genome-wide association studies (GWASs) of BP traits accounting for gene-depressive symptomatology (DEPR) interactions. Our study included 564,680…

Variant selection to maximize variance explained in cis-Mendelian randomization

Ang Zhou; Ville Karhunen; Haodong Tian et al.

HGG Advances, Vol. 7 No. 2 · 2026 · English · DOAJ Scopus

Summary: Optimal selection of instrumental variables (IVs) from a single gene region in cis-Mendelian randomization (MR) is challenging, as variants are highly correlated due to linkage disequilibrium (LD). Using only the lead variant is convenient but may not achieve full statistical power if…

EEFSEC deficiency underlies a human selenopathy with primary neurodevelopmental origins via midbrain-hindbrain hypoplasia

Zhiyi Xia; Hui Liu; Pengbo Guo et al.

HGG Advances, Vol. 7 No. 2 · 2026 · English · DOAJ Scopus

Summary: Bi-allelic mutations in EEFSEC, a key factor in selenoprotein synthesis, cause a severe human selenopathy characterized by developmental delay, spasticity, and profound cerebellar atrophy. While previous studies in invertebrate models framed this condition as an early-onset…

Germline HLA heterozygosity is associated with decreased lung cancer risk

Taotao Tan; Vikram R. Shaw; Jinyoung Byun et al.

HGG Advances, Vol. 7 No. 2 · 2026 · English · DOAJ Scopus

Summary: Heterozygosity at human leukocyte antigen (HLA) loci may improve lung cancer immunosurveillance by increasing recognition of the tumor by the immune system. Previous studies utilizing data from population-level biobanks, such as the United Kingdom Biobank and FinnGen, have identified an…

Interplay between genomic architecture alterations and GDF6 regulation: A candidate mechanism in Nablus mask-like facial syndrome

Alexandru Marian Bologa; Luiza Dimos; Anca Gabriela Pavel et al.

HGG Advances, Vol. 7 No. 4 · 2026 · English · DOAJ Scopus

Summary: Nablus mask-like facial syndrome (NMLFS) is a very rare disorder associated with 8q22.1q22 microdeletions and characterized by a distinctive facial phenotype and variable neurological, cardiological, and genital anomalies. However, not all affected individuals with overlapping deletions…

Expanding the ABCA2-associated neurodevelopmental phenotype

Kaisa T. Oja; Karit Reinson; Mihkel Ilisson et al.

HGG Advances, Vol. 7 No. 4 · 2026 · English · DOAJ Scopus

Summary: The ATP-binding cassette subfamily A member 2 (ABCA2) gene encodes an ABC transporter protein. Bi-allelic loss-of-function variants in ABCA2 have been associated with an intellectual disability disorder. We aimed to delineate the phenotypic spectrum of individuals with monoallelic (MV) or…

Targeted plasma proteomics uncover proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders

Jarosław Dulski; Arun K. Boddapati; Barbara Risi et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: KIF5A (Kinesin family member 5A) is a motor protein that functions as a key component of the axonal transport machinery. Variants in KIF5A are linked to several neurodegenerative diseases, mainly spastic paraplegia type 10 (SPG10), Charcot-Marie-Tooth disease type 2 (CMT2), and amyotrophic…

Asparaginyl-tRNA synthetase (NARS1) variants implicated in dominant neurological phenotypes display dominant-negative properties

Sheila M. Peeples; Keyana Blake; Brendan L.M. Sutton et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: Aminoacyl-tRNA synthetases (ARSs) are essential, ubiquitously expressed enzymes that ligate amino acids to cognate tRNAs in the cytoplasm and mitochondria. To date, seven dimeric ARS enzymes have been implicated in dominant inherited neuropathy, suggesting that tRNA charging—exacerbated by…

The Karnataka Individual Genome Project expands the human reference landscape to include South Asia

Apoorva Ganesh; Anisha Mhatre; Yash Chindarkar et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: Assembling individual genomes remains an expensive endeavor, hindering large-scale comparative human genomics. So far, chromosome-level assemblies of only a few individuals, including PR1 (Puerto Rican), Ash1 (Ashkenazi Jew), Han1 (Southern Han Chinese), and CHM13 (Northern European) have…

Phasing millions of samples achieves near perfect accuracy, enabling parent-of-origin analyses

Cole M. Williams; Jared O’Connell; Ethan Jewett et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Genome-wide association study reveals genetic mechanisms underlie eye disorders and comorbidities

Chia-Ni Hsiung; Wen-Cheng Chou; Chih-Hsiung Hsu et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: Eye diseases, including cataracts, glaucoma, diabetes retinopathy, and age-related macular degeneration, are major global health challenges and leading causes of blindness. This study leveraged genome-wide association studies (GWASs) involving over 100,000 individuals, integrating data…

Bi-allelic INTU variants define a ciliopathy disorder characterized by orofacial, digital, and cardiac anomalies

Rebekah Rushforth; Kurt Reynolds; Steven I. Estes et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: The primary cilium is a small organelle that plays key roles in cellular signaling. Defects in primary cilia formation, morphology, and function cause a heterogeneous group of developmental syndromes termed ciliopathies. The inturned planar cell polarity protein (INTU) gene acts in the…

Aberrant N-glycosylation may be a therapeutic target in carriers of a common and highly pleiotropic variant in the manganese transporter ZIP8

Vartika Tomar; John Kang; Ruxian Lin et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: The treatment of defective glycosylation in clinical practice has been limited to patients with rare and severe phenotypes associated with congenital disorders of glycosylation (CDGs). Carried by approximately 5% of the human population, the discovery of the highly pleiotropic, missense…

PATJ deficiency leads to cystic kidney disease and related ciliopathies

Daniel Epting; Daniela A. Braun; Eva Decker et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: Cystic kidney disease and related ciliopathies are caused by pathogenic variants in genes that commonly result in ciliary dysfunction. For a substantial number of individuals affected by those cilia-related diseases, the causative gene remains unknown. Using massively parallel sequencing…

Pathway-specific polygenic scores substantially increase the discovery of gene-adiposity interactions impacting liver biomarkers

Kenneth E. Westerman; Daniel I. Chasman; W. James Gauderman et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: Polygenic scores (PGSs) are appealing for detecting gene-environment interactions due to the aggregation of genetic effects and reduced multiple testing burden compared to single-variant genome-wide interaction studies (GWISs). However, standard PGSs reflect many different biological…

A systematic assessment of large language models’ knowledge of rare diseases: How much do large language models know about rare disease?

Tudor Groza; Allison J. Marcello; Tristan Carlisle et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: Large language models (LLMs) perform well on general medical benchmarks, but their ability to reason about rare diseases (RDs) remains unclear. Rather than challenge LLMs to diagnose a limited number of cases that are unlikely to represent all RDs or RD-associated genes, we instead sought…

Unexpectedly high levels of normally spliced transcripts from the pathogenic SLC10A7 alleles in a recessive form of skeletal dysplasia

Xing-Chen Zhao; Zhen-Cong Zhang; Wen-Lin Ye et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: Bi-allelic loss-of-function (LoF) variants in SLC10A7 cause short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS). Here, we report findings from an individual of Chinese ancestry with SSASKS carrying compound heterozygous splice-altering SLC10A7 variants: a…

Splicing and frameshift variants in QSER1 may be involved in developmental phenotypes

Megan C. Fischer; Linda M. Reis; Jerica Lenberg et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: Human development is a complex process that requires precise control of gene expression through regulatory proteins. Recently, heterozygous variants in PRR12, encoding a proline-rich regulatory protein, were found to cause a variable phenotype involving developmental delay/cognitive…

Functional characterization of pathogenic SATB2 missense variants identifies distinct effects on chromatin binding and transcriptional activity

Joery den Hoed; Fleur Semmekrot; Jolijn Verseput et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: SATB2-associated syndrome is an autosomal dominant neurodevelopmental syndrome caused by genetic alterations in the transcription factor SATB2. The associated phenotype is variable, and genotype-phenotype correlation studies have not yet been able to explain differences in severity and…

Detailed assessment of rare and common TERT variation in a family with a telomere biology disorder

Logan P. Zeigler; Oscar Florez-Vargas; Burak Altintas et al.

HGG Advances, Vol. 7 No. 1 · 2026 · English · DOAJ Scopus

Summary: Telomere biology disorders (TBDs) are caused by rare pathogenic variants in telomere maintenance genes and often present with variable penetrance of multi-organ system manifestations. We evaluated a family with 14 individuals heterozygous for TERT c.2591T>C (p.L864P) and 13 non-carriers…