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Up to 80% of rare disease patients remain undiagnosed after genomic sequencing 1 , with many probably involving pathogenic variants in yet to be discovered disease-gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project 2 . A total of 141 new associations were identified, including five for which independent disease-gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence. The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator 3,4 UNC13A, schizophrenia with GPR17, epilepsy with RBFOX3, Charcot-Marie-Tooth disease with ARPC3 and anterior segment ocular abnormalities with POMK. Further confirmation of these and other associations could lead to numerous diagnoses, highlighting the clinical impact of large-scale statistical approaches to rare disease-gene association discovery., Competing Interests: Competing interests: The authors declare the following competing interests: D.S. and M.C. were seconded to, and received salary from, Genomics England, a wholly owned Department of Health and Social Care company, from 2016 to 2018 and 2013 to 2021, respectively. E.A.O. has research funding from Kamari Pharma, Pavella Therapeutics, Unilever and the Leo Foundation unrelated to this work. She is CI for a trial for Kamari Pharma and performs consultancy for Kamari Pharma, Azitra and Palvella Therapeutics (all money goes to the university). S.L.Z. has provided consultancy services to Health Lumen. All other authors declare no competing interests., (© 2025. The Author(s).)

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2, at least 8 others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear., Methods: We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100kGP (100kGP), UK Biobank (UKBB), and Mayo Clinic Biobank (MCBB)), were screened for ALG8/ALG9 pathogenic variants., Results: Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families; frequencies that were ∼10x and ∼24x greater than non-polycystic kidney disease (PKD) controls. Analysis of individuals with PKD phenotypes in 100kGP, UKBB, and MCBB identified 9 ALG8 (0.39%) and 9 ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (56%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%) with enlarged livers (>2L) found in 11/62 patients although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys but enlarged livers were rare; for both genes chronic kidney disease or kidney failure were rare., Conclusions: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR., (Copyright © 2025 by the American Society of Nephrology.)

Purpose: In parent-child trios with genome sequencing data, we investigated inherited biallelic deletions to identify known and novel genetic disorders., Methods: We developed a copy-number variations analysis pipeline based on autosomal genome sequencing read depth of Genomics England 100,000 Genomes Project data from 11,754 parent-child trios and additional 18,875 non-trios. A control cohort of 15,440 cancer patients provided independent deletion frequencies., Results: Autosomal recessive (AR) modeling detected 34 distinct rare deletions that were homozygous in the proband and heterozygous in both parents. These inherited biallelic deletions were only detected in 52 trios. These "knockout" regions included 37 genes, having among them 8 with an Online Mendelian Inheritance in Man AR annotation. Deletions of NPHP1 , followed by OTOA , both within segmental duplications, were the only recurrent findings explaining phenotypes in a total of 10 and 3 patients, respectively. Recurrent heterozygous NPHP1 deletions were detected in 0.3%-0.5% of controls. We reviewed "knockout" patients for the remaining 29 genes without disease associations and identified SLC66A1 as a likely novel cause for AR rod-cone dystrophy in 4 families., Conclusion: A tailored copy-number variations analysis of genome sequencing trio data shows that biallelic inherited gene deletions are rare, with NPHP1 biallelic deletions causing nephronophthisis the leading finding. We propose SLC66A1 as a novel cause for AR retinopathy., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Introduction: Massively parallel sequencing (MPS) techniques have made a major impact on the identification of the genetic basis of inherited kidney diseases such as the ciliopathy autosomal dominant polycystic kidney disease (ADPKD). Great care must be taken when analysing MPS data in isolation from accurate phenotypic information, as this can cause misdiagnosis., Methods: Here, we describe a family trio, recruited to the Genomics England 100,000 Genomes Project, labelled as having cystic kidney disease, who were genetically unsolved following routine data analysis pipelines. We performed a bespoke reanalysis of Whole Genome Sequencing (WGS) data and coupled this with revised phenotypic data and targeted PCR and Sanger sequencing to provide a precise molecular genetic diagnosis., Results: We detected a heterozygous PKD1 frameshift variant within the WGS data which segregated with the redefined ADPKD phenotypes. An additional heterozygous exon deletion in ALG8 was also found in affected and unaffected individuals, but its precise clinical significance remains unclear., Conclusion: This case illustrates that reanalysis of WGS data in unsolved cases of cystic kidney disease is valuable. Clinical phenotypes must be reassessed as these may have been incorrectly recorded and evolve over time. Undertaking additional studies including genotype-phenotype correlation in wider family members provides useful diagnostic information., (© 2023 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.)

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of β cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.

While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Ciliopathies may be classed as primary or motile depending on the underlying ciliary defect and are usually considered distinct clinical entities. Primary ciliopathies are associated with multisystem syndromes typically affecting the brain, kidney, and eye, as well as other organ systems such as the liver, skeleton, auditory system, and metabolism. Motile ciliopathies are a heterogenous group of disorders with defects in specialised motile ciliated tissues found within the lung, brain, and reproductive system, and are associated with primary ciliary dyskinesia, bronchiectasis, infertility and rarely hydrocephalus. Primary and motile cilia share defined core ultra-structures with an overlapping proteome, and human disease phenotypes can reflect both primary and motile ciliopathies. CEP164 encodes a centrosomal distal appendage protein vital for primary ciliogenesis. Human CEP164 mutations are typically described in patients with nephronophthisis-related primary ciliopathies but have also been implicated in motile ciliary dysfunction. Here we describe a patient with an atypical motile ciliopathy phenotype and biallelic CEP164 variants. This work provides further evidence that CEP164 mutations can contribute to both primary and motile ciliopathy syndromes, supporting their functional and clinical overlap, and informs the investigation and management of CEP164 ciliopathy patients., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Objectives/aims: The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle. They manifest in both the GI and GU tracts, ranging from megacystis to Prune Belly syndrome. We aimed to apply a bespoke virtual genetic panel and describe novel variants associated with this condition using whole genome sequencing data within the Genomics England 100,000 Genomes Project., Methods: We screened the Genomics England 100,000 Genomes Project rare diseases database for patients with VM-related phenotypes. These patients were screened for sequence variants and copy number variants (CNV) in ACTG2 , ACTA2 , MYH11 , MYLK , LMOD1 , CHRM3 , MYL9 , FLNA and KNCMA1 by analysing whole genome sequencing data. The identified variants were analysed using variant effect predictor online tool, and any possible segregation in other family members and novel missense mutations was modelled using in silico tools. The VM cohort was also used to perform a genome-wide variant burden test in order to identify confirm gene associations in this cohort., Results: We identified 76 patients with phenotypes consistent with a diagnosis of VM. The range of presentations included megacystis/microcolon hypoperistalsis syndrome, Prune Belly syndrome and chronic intestinal pseudo-obstruction. Of the patients in whom we identified heterozygous ACTG2 variants, 7 had likely pathogenic variants including 1 novel likely pathogenic allele. There were 4 patients in whom we identified a heterozygous MYH11 variant of uncertain significance which leads to a frameshift and a predicted protein elongation. We identified one family in whom we found a heterozygous variant of uncertain significance in KCNMA1 which in silico models predicted to be disease causing and may explain the VM phenotype seen. We did not find any CNV changes in known genes leading to VM-related disease phenotypes. In this phenotype selected cohort, ACTG2 is the largest monogenic cause of VM-related disease accounting for 9% of the cohort, supported by a variant burden test approach, which identified ACTG2 variants as the largest contributor to VM-related phenotypes., Conclusions: VM are a group of disorders that are not easily classified and may be given different diagnostic labels depending on their phenotype. Molecular genetic analysis of these patients is valuable as it allows precise diagnosis and aids understanding of the underlying disease manifestations. We identified ACTG2 as the most frequent genetic cause of VM. We recommend a nomenclature change to 'autosomal dominant ACTG2 visceral myopathy' for patients with pathogenic variants in ACTG2 and associated VM phenotype s ., Supplementary Information: The online version contains supplementary material available at 10.1007/s44162-023-00012-z., Competing Interests: Competing interestsProfessor John Sayer is a co-author of this study and editorial board member of the journal. He was not involved in handling this manuscript during the review process. The rest of the authors declare that they have no competing interests., (© The Author(s) 2023.)

LncRNAs are involved in regulatory processes in the human genome, including gene expression. The rs35705950 SNP, previously associated with IPF, overlaps with the recently annotated lncRNA AC061979.1, a 1712 nucleotide transcript located within the MUC5B promoter at chromosome 11p15.5. To document the expression pattern of the transcript, we processed 3.9 TBases of publicly available RNA-SEQ data across 27 independent studies involving lung airway epithelial cells. Epithelial lung cells showed expression of this putative pancRNA. The findings were independently validated in cell lines and primary cells. The rs35705950 is found within a conserved region (from fish to primates) within the expressed sequence indicating functional importance. These results implicate the rs35705950-containing AC061979.1 pancRNA as a novel component of the MUC5B expression control minicircuitry.

Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (∼78% and ∼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype. In a multi-cohort/-site collaboration, we screened ADPKD-diagnosed families that were naive to genetic testing (n = 834) or for whom no PKD1 and PKD2 pathogenic variants had been identified (n = 381) with a PKD targeted next-generation sequencing panel (tNGS; n = 1,186) or whole-exome sequencing (WES; n = 29). We identified monoallelic IFT140 loss-of-function (LoF) variants in 12 multiplex families and 26 singletons (1.9% of naive families). IFT140 is a core component of the intraflagellar transport-complex A, responsible for retrograde ciliary trafficking and ciliary entry of membrane proteins; bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9). The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts. Analyses of the cystic kidney disease probands of Genomics England 100K showed that 2.1% had IFT140 LoF variants. Analysis of the UK Biobank cystic kidney disease group showed probands with IFT140 LoF variants as the third most common group, after PKD1 and PKD2. The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype. Importantly, our studies link a ciliary structural protein to the ADPKD spectrum., Competing Interests: Declaration of interests M.M. reports grants and consulting fees outside the submitted work from Otsuka Pharmaceuticals, Sanofi, Chinook, Goldilocks, Natera, and Palladio. R.D.P. reports clinical trial support from Reata, Kadmon, Sanofi-Genzyme, US Department of Defense; consultant/advisory fees from Otsuka and Sanofi-Genzyme; and is section editor Renal Cystic Disease: UpToDate. J.A.S. has received honorarium from consulting positions from Otsuka Pharmaceuticals, Sanofi, and Takeda. V.E.T. reports grants and/or other fees from Mironid, Blueprint Medicines, Otsuka Pharmaceuticals, Palladio Biosciences, Sanofi Genzyme, Reata, and Regulus Therapeutics, all outside the submitted work., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)