A genome-wide association study identifies a susceptibility locus for biliary atresia on 2p16.1 within the gene EFEMP1

Biliary atresia (BA) is a rare pediatric cholangiopathy characterized by fibrosclerosing obliteration of the extrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and eventual liver failure. The etiology of BA remains unknown, although environmental, inflammatory, infectious, and genetic risk factors have been proposed. We performed a genome-wide association study (GWAS) in a European-American cohort of 343 isolated BA patients and 1716 controls to identify genetic loci associated with BA. A second GWAS was performed in an independent European-American cohort of 156 patients with BA and other extrahepatic anomalies and 212 controls to confirm the identified candidate BA-associated SNPs. Meta-analysis revealed three genome-wide significant BA-associated SNPs on 2p16.1 (rs10865291, rs6761893, and rs727878; P < 5 ×10-8), located within the fifth intron of the EFEMP1 gene, which encodes a secreted extracellular protein implicated in extracellular matrix remodeling, cell proliferation, and organogenesis. RNA expression analysis showed an increase in EFEMP1 transcripts from human liver specimens isolated from patients with either BA or other cholestatic diseases when compared to normal control liver samples. Immunohistochemistry demonstrated that EFEMP1 is expressed in cholangiocytes and vascular smooth muscle cells in liver specimens from patients with BA and other cholestatic diseases, but it is absent from cholangiocytes in normal control liver samples. Efemp1 transcripts had higher expression in cholangiocytes and portal fibroblasts as compared with other cell types in normal rat liver. The identification of a novel BA-associated locus, and implication of EFEMP1 as a new BA candidate susceptibility gene, could provide new insights to understanding the mechanisms underlying this severe pediatric disorder

Rare Variant Enrichment analysis Supports

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, onl

Bedrock geology of DFDP-2B, central Alpine Fault, New Zealand

<p>During the second phase of the Alpine Fault, Deep Fault Drilling Project (DFDP) in the Whataroa River, South Westland, New Zealand, bedrock was encountered in the DFDP-2B borehole from 238.5–893.2 m Measured Depth (MD). Continuous sampling and meso- to microscale characterisation of whole rock cuttings established that, in sequence, the borehole sampled amphibolite facies, Torlesse Composite Terrane-derived schists, protomylonites and mylonites, terminating 200–400 m above an Alpine Fault Principal Slip Zone (PSZ) with a maximum dip of 62°. The most diagnostic structural features of increasing PSZ proximity were the occurrence of shear bands and reduction in mean quartz grain sizes. A change in composition to greater mica:quartz + feldspar, most markedly below c. 700 m MD, is inferred to result from either heterogeneous sampling or a change in lithology related to alteration. Major oxide variations suggest the fault-proximal Alpine Fault alteration zone, as previously defined in DFDP-1 core, was not sampled.</p

Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis

Purpose: We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. Methods: Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope. Results: We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation. Conclusion: In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.US National Institute of Neurological Disorders and Stroke [R35 NS 105078]; US National Human Genome Research Institute (NHGRI); National Heart, Lung, and Blood Institute [UM1 HG006542, R01 GM106373, U01 HG011758, 512848]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health [P50HD103555]; International Rett Syndrome Foundation (IRSF) [3701-1]; NHGRI [K08 HG008986]; German Research Council (DFG) [KO 2891/9-1]; BIH Center for Regenerative Therapies (BCRT)We are grateful to the families for their participation in this study. We thank Aris. N. Economides and Manuel Holtgrewe for their valuable suggestions and support. J.R.L. laboratory is supported by the US National Institute of Neurological Disorders and Stroke (R35 NS 105078) and in part by the US National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG; UM1 HG006542), the National Institute of General Medical Sciences (NIGMS; R01 GM106373), the NHGRI Baylor College of Medicine Genomics Research Elucidates Genetics of Rare Diseases (BCM-GREGoR; U01 HG011758), the Muscular Dystrophy Association (512848), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health under award number P50HD103555 for use of the Clinical Translation Core facilities. D.P. is supported by International Rett Syndrome Foundation (IRSF; grant #3701-1). J.E.P. was supported by NHGRI K08 HG008986. U.K. obtained funding from the German Research Council (DFG)(KO 2891/9-1) and the BIH Center for Regenerative Therapies (BCRT)(cross-field project GenoPro)

Paralog Studies Augment Gene Discovery: DDX and DHX Genes

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [UM1 HG006542, UM1 HG006493]; National Heart, Lung, and Blood Institute (NHLBI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI); University of Washington Center for Mendelian Genomics [R01 NS058529, R35 NS105078]; National Institute of Neurological Disorders and Stroke (NINDS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS); NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08 HG008986]; Telethon Undiagnosed Diseases Program [GSP15001]; Telethon FoundationFondazione Telethon; Aicardi Syndrome Foundation [2T32NS043124-16]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [DK088767]; Werner Otto Stiftung [K12 DK083014]; German Research Foundation (DFG)German Research Foundation (DFG) [LE 4223/1]; Common Fund of the Office of the Director of the National Institutes of Health; National Cancer Institute, NHGRI; NHLBIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI); National Institute on Drug AbuseUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA)European Commission; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH); NINDSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS); NATIONAL HUMAN GENOME RESEARCH INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08HG008986, UM1HG006542] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [T32GM008307] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078] Funding Source: NIH RePORTERThis work was supported in part by grants UM1 HG006542 (J.R.L) and UM1 HG006493 (M.B.) from the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI) to the Baylor Hopkins Center for Mendelian Genomics and the University of Washington Center for Mendelian Genomics, R01 NS058529 and R35 NS105078(J.R.L.) from the National Institute of Neurological Disorders and Stroke (NINDS), U54-HG003273 (R.A.G.) from NHGRI, and Telethon Undiagnosed Diseases Program (TUDP) GSP15001 (N.B.-P.) from the Telethon Foundation, and also by the Aicardi Syndrome Foundation. I.P. was supported by 2T32NS043124-16 through the National Institutes of Health. J.E.P. was supported by NHGRI K08 HG008986. F.H. was supported by the National Institutes of Health (DK088767). M.R.B. was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) K12 DK083014. D.L was supported by the Werner Otto Stiftung and the German Research Foundation (DFG; LE 4223/1). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the National Cancer Institute, NHGRI, NHLBI, the National Institute on Drug Abuse, the National Institute of Mental Health, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/29/18. The authors would like to thank Hans-Jurgen Kreienkamp for the help in identifying helicase core motifs and the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about

CHRNA7 copy number gains are enriched in adolescents with major depressive and anxiety disorders

Objective: Neuronal nicotinic acetylcholine receptors (nAChRs), specifically the alpha 7 nAChR encoded by the gene CHRNA7, have been implicated in behavior regulation in animal models. In humans, copy number variants (CNVs) of CHRNA7 are found in a range of neuropsychiatric disorders, including mood and anxiety disorders. Here, we aimed to determine the prevalence of CHRNA7 CNVs among adolescents and young adults with major depressive disorder (MDD) and anxiety disorders. Methods: Twelve to 21 year-old participants with MDD and/or anxiety disorders (34% males, mean +/- std age: 18.9 +/- 1.8 years) were assessed for CHRNA7 copy number state using droplet digital PCR (ddPCR) and genomic quantitative PCR (qPCR). Demographic, anthropometric, and clinical data, including the Beck Anxiety Index (BAI), Beck Depression Inventory (BDI), and the Inventory of Depressive Symptoms (IDS) were collected and compared across individuals with and without a CHRNA7 CNV. Results: Of 205 individuals, five (2.4%) were found to carry a CHRNA7 gain, significantly higher than the general population. No CHRNA7 deletions were identified. Clinically, the individuals carrying CHRNA7 duplications did not differ significantly from copy neutral individuals with MDD and/or anxiety disorders. Conclusions: CHRNA7 gains are relatively prevalent among young individuals with MDD and anxiety disorders (odds ratio = 4.032) without apparent distinguishing clinical features. Future studies should examine the therapeutic potential of a7 nAChR targeting drugs to ameliorate depressive and anxiety disorders

Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia

Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277 kb heterozygous deletion on chromosome 20, which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband

Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia

In the United States, biliary atresia (BA) is the most frequent indication for liver transplantation in pediatric patients. BA is a complex disease, with suspected environmental and genetic risk factors. A genome-wide association study in Chinese patients identified association to the 10q24.2 (hg18) genomic region. This signal was upstream of two genes, XPNPEP1 and ADD3, both expressed in intrahepatic bile ducts. We tested association to this region in 171 BA patients and 1,630 controls of European descent and found the strongest signal to be at rs7099604 (p = 2.5 x 10(-3)) in intron 1 of the ADD3 gene. Moreover, expression data suggest that ADD3, but not XPNPEP1, is differentially expressed in BA patients. The role of ADD3 in biliary development is unclear, but our findings suggest that this gene may be functionally relevant for the development of BA

A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report

Background: Children with very early-onset inflammatory bowel disease (VEO-IBD), those diagnosed at less than 5 years of age, are a unique population. A subset of these patients present with a distinct phenotype and more severe disease than older children and adults. Host genetics is thought to play a more prominent role in this young population, and monogenic defects in genes related to primary immunodeficiencies are responsible for the disease in a small subset of patients with VEO-IBD.Case Presentation: We report a child who presented at 3 weeks of life with very early-onset inflammatory bowel disease (VEO-IBD). He had a complicated disease course and remained unresponsive to medical and surgical therapy. The refractory nature of his disease, together with his young age of presentation, prompted utilization of whole exome sequencing (WES) to detect an underlying monogenic primary immunodeficiency and potentially target therapy to the identified defect. Copy number variation analysis (CNV) was performed using the eXome-Hidden Markov Model. Whole exome sequencing revealed 1,380 nonsense and missense variants in the patient. Plausible candidate variants were not detected following analysis of filtered variants, therefore, we performed CNV analysis of the WES data, which led us to identify a de novo whole gene deletion in XIAP.Conclusion: This is the first reported whole gene deletion in XIAP, the causal gene responsible for XLP2 (X-linked lymphoproliferative Disease 2). XLP2 is a syndrome resulting in VEO-IBD and can increase susceptibility to hemophagocytic lymphohistocytosis (HLH). This identification allowed the patient to be referred for bone marrow transplantation, potentially curative for his disease and critical to prevent the catastrophic sequela of HLH. This illustrates the unique etiology of VEO-IBD, and the subsequent effects on therapeutic options. This cohort requires careful and thorough evaluation for monogenic defects and primary immunodeficiencies