Publications by authors named "Richard A Gibbs"

514 Publications

Exome variant discrepancies due to reference genome differences.

Am J Hum Genet 2021 Jun 11. Epub 2021 Jun 11.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Despite release of the GRCh38 human reference genome more than seven years ago, GRCh37 remains more widely used by most research and clinical laboratories. To date, no study has quantified the impact of utilizing different reference assemblies for the identification of variants associated with rare and common diseases from large-scale exome-sequencing data. By calling variants on both the GRCh37 and GRCh38 references, we identified single-nucleotide variants (SNVs) and insertion-deletions (indels) in 1,572 exomes from participants with Mendelian diseases and their family members. We found that a total of 1.5% of SNVs and 2.0% of indels were discordant when different references were used. Notably, 76.6% of the discordant variants were clustered within discrete discordant reference patches (DISCREPs) comprising only 0.9% of loci targeted by exome sequencing. These DISCREPs were enriched for genomic elements including segmental duplications, fix patch sequences, and loci known to contain alternate haplotypes. We identified 206 genes significantly enriched for discordant variants, most of which were in DISCREPs and caused by multi-mapped reads on the reference assembly that lacked the variant call. Among these 206 genes, eight are implicated in known Mendelian diseases and 53 are associated with common phenotypes from genome-wide association studies. In addition, variant interpretations could also be influenced by the reference after lifting-over variant loci to another assembly. Overall, we identified genes and genomic loci affected by reference assembly choice, including genes associated with Mendelian disorders and complex human diseases that require careful evaluation in both research and clinical applications.
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http://dx.doi.org/10.1016/j.ajhg.2021.05.011DOI Listing
June 2021

Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature.

Front Pediatr 2021 20;9:673957. Epub 2021 May 20.

Facultad de Medicina Universidad del Desarrollo-Clínica Alemana, Santiago, Chile.

Lysinuric protein intolerance (LPI) is an inborn error of metabolism caused by defective transport of cationic amino acids in epithelial cells of intestines, kidneys and other tissues as well as non-epithelial cells including macrophages. LPI is caused by biallelic, pathogenic variants in . The clinical phenotype of LPI includes failure to thrive and multi-system disease including hematologic, neurologic, pulmonary and renal manifestations. Individual presentations are extremely variable, often leading to misdiagnosis or delayed diagnosis. Here we describe a patient that clinically presented with immune dysregulation in the setting of early-onset systemic lupus erythematosus (SLE), including renal involvement, in whom an LPI diagnosis was suspected post-mortem based on exome sequencing analysis. A review of the literature was performed to provide an overview of the clinical spectrum and immune mechanisms involved in this disease. The precise mechanism by which ineffective amino acid transport triggers systemic inflammatory features is not yet understood. However, LPI should be considered in the differential diagnosis of early-onset SLE, particularly in the absence of response to immunosuppressive therapy.
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http://dx.doi.org/10.3389/fped.2021.673957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172984PMC
May 2021

Risk of sudden cardiac death in EXOSC5-related disease.

Am J Med Genet A 2021 Jun 4. Epub 2021 Jun 4.

Department of Pediatrics, Division of Cardiology, Texas Children's Hospital, Houston, Texas, USA.

The RNA exosome is a multi-subunit complex involved in the processing, degradation, and regulated turnover of RNA. Several subunits are linked to Mendelian disorders, including pontocerebellar hypoplasia (EXOSC3, MIM #614678; EXOSC8, MIM #616081: and EXOSC9, MIM #618065) and short stature, hearing loss, retinitis pigmentosa, and distinctive facies (EXOSC2, MIM #617763). More recently, EXOSC5 (MIM *606492) was found to underlie an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies. An unusual feature of EXOSC5-related disease is the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals. Here, we provide a detailed clinical and molecular characterization of two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination, with cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT) due to compound heterozygous variants in EXOSC5: (1) NM_020158.4:c.341C > T (p.Thr114Ile; pathogenic, previously reported) and (2) NM_020158.4:c.302C > A (p.Thr101Lys; novel variant). A review of the literature revealed an additional family with biallelic EXOSC5 variants and cardiac conduction abnormalities. These clinical and molecular data provide compelling evidence that cardiac conduction abnormalities and arrhythmias are part of the EXOSC5-related disease spectrum and argue for proactive screening due to potential risk of sudden cardiac death.
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http://dx.doi.org/10.1002/ajmg.a.62352DOI Listing
June 2021

Biallelic Pathogenic Variants in Associated With Congenital Myopathy.

Neurol Genet 2021 Jun 26;7(3):e589. Epub 2021 Apr 26.

Division of Neurology and Developmental Neuroscience (D.G.C., I.H., D.P., T.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital (D.G.C., I.H., D.P., J.R.L.), Houston, TX; Department of Molecular and Human Genetics (D.G.C., J.F., I.H., Z.C.A., H.D., R.A.G., D.M., D.P., J.E.P., J.R.L.), Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center (S.N.J., R.A.G., J.R.L.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (D.M.), Faculty of Medicine, Kuwait University, Safat, Kuwait; Division of Child and Adolescent Neurology (P.M.), Department of Pediatrics, University of Texas Health Science Center, Houston, TX; Pathology and Laboratory Medicine (M.B.B.), University of Texas Health Science Center at Houston-McGovern Medical School, Houston, TX; and Department of Pediatrics (J.R.L.), Baylor College of Medicine, Houston, TX.

Objective: Pathogenic variants in , the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic variants.

Methods: Clinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with -related congenital myopathy.

Results: A homozygous variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with -related congenital myopathy, were not observed in the patient reported here.

Conclusions: This report provides further evidence for the association of biallelic variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.
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http://dx.doi.org/10.1212/NXG.0000000000000589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105884PMC
June 2021

Genomic considerations for FHIR®; eMERGE implementation lessons.

J Biomed Inform 2021 Jun 28;118:103795. Epub 2021 Apr 28.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Structured representation of clinical genetic results is necessary for advancing precision medicine. The Electronic Medical Records and Genomics (eMERGE) Network's Phase III program initially used a commercially developed XML message format for standardized and structured representation of genetic results for electronic health record (EHR) integration. In a desire to move towards a standard representation, the network created a new standardized format based upon Health Level Seven Fast Healthcare Interoperability Resources (HL7® FHIR®), to represent clinical genomics results. These new standards improve the utility of HL7® FHIR® as an international healthcare interoperability standard for management of genetic data from patients. This work advances the establishment of standards that are being designed for broad adoption in the current health information technology landscape.
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http://dx.doi.org/10.1016/j.jbi.2021.103795DOI Listing
June 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

A novel homozygous SLC13A5 whole-gene deletion generated by Alu/Alu-mediated rearrangement in an Iraqi family with epileptic encephalopathy.

Am J Med Genet A 2021 Jul 2;185(7):1972-1980. Epub 2021 Apr 2.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Biallelic loss-of-function (LoF) of SLC13A5 (solute carrier family 13, member 5) induced deficiency in sodium/citrate transporter (NaCT) causes autosomal recessive developmental epileptic encephalopathy 25 with hypoplastic amelogenesis imperfecta (DEE25; MIM #615905). Many pathogenic SLC13A5 single nucleotide variants (SNVs) and small indels have been described; however, no cases with copy number variants (CNVs) have been sufficiently investigated. We describe a consanguineous Iraqi family harboring an 88.5 kb homozygous deletion including SLC13A5 in Chr17p13.1. The three affected male siblings exhibit neonatal-onset epilepsy with fever-sensitivity, recurrent status epilepticus, global developmental delay/intellectual disability (GDD/ID), and other variable neurological findings as shared phenotypical features of DEE25. Two of the three affected subjects exhibit hypoplastic amelogenesis imperfecta (AI), while the proband shows no evidence of dental abnormalities or AI at 2 years of age with apparently unaffected primary dentition. Characterization of the genomic architecture at this locus revealed evidence for genomic instability generated by an Alu/Alu-mediated rearrangement; confirmed by break-point junction Sanger sequencing. This multiplex family from a distinct population elucidates the phenotypic consequence of complete LoF of SLC13A5 and illustrates the importance of read-depth-based CNV detection in comprehensive exome sequencing analysis to solve cases that otherwise remain molecularly unsolved.
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http://dx.doi.org/10.1002/ajmg.a.62192DOI Listing
July 2021

Germline mutation in : a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.

HGG Adv 2021 Jan 20;2(1). Epub 2020 Nov 20.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

germline variation in was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic or inherited variants in , detail their phenotypes, and map all known variants to the domain structure of and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). -related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.
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http://dx.doi.org/10.1016/j.xhgg.2020.100014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928427PMC
January 2021

Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome.

Hum Mutat 2021 May 6;42(5):577-591. Epub 2021 Mar 6.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

Xia-Gibbs syndrome (XGS) is a rare Mendelian disease typically caused by de novo stop-gain or frameshift mutations in the AT-hook DNA binding motif containing 1 (AHDC1) gene. Patients usually present in early infancy with hypotonia and developmental delay and later exhibit intellectual disability (ID). The overall presentation is variable, however, and the emerging clinical picture is still evolving. A detailed phenotypic analysis of 34 XGS individuals revealed five core phenotypes (delayed motor milestones, speech delay, low muscle tone, ID, and hypotonia) in more than 80% of individuals and an additional 12 features that occurred more variably. Seizures and scoliosis were more frequently associated with truncations that arise before the midpoint of the protein although the occurrence of most features could not be predicted by the mutation position. Transient expression of wild type and different patient truncated AHDC1 protein forms in human cell lines revealed abnormal patterns of nuclear localization including a diffuse distribution of a short truncated form and nucleolar aggregation in mid-protein truncated forms. Overall, both the occurrence of variable phenotypes and the different distribution of the expressed protein reflect the heterogeneity of this syndrome.
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http://dx.doi.org/10.1002/humu.24190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115934PMC
May 2021

RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes.

Mol Psychiatry 2021 05 17;26(5):1706-1718. Epub 2021 Feb 17.

The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3'-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.
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http://dx.doi.org/10.1038/s41380-021-01035-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159744PMC
May 2021

Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant.

Am J Med Genet A 2021 04 5;185(4):1288-1293. Epub 2021 Feb 5.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Alkylated DNA repair protein AlkB homolog 8 (ALKBH8) is a member of the AlkB family of dioxygenases. ALKBH8 is a methyltransferase of the highly variable wobble nucleoside position in the anticodon loop of tRNA and thus plays a critical role in tRNA modification by preserving codon recognition and preventing errors in amino acid incorporation during translation. Moreover, its activity catalyzes uridine modifications that are proposed to be critical for accurate protein translation. Previously, two distinct homozygous truncating variants in the final exon of ALKBH8 were described in two unrelated large Saudi Arabian kindreds with intellectual developmental disorder and autosomal recessive 71 (MRT71) syndrome (MIM# 618504). Here, we report a third family-of Egyptian descent-harboring a novel homozygous frame-shift variant in the last exon of ALKBH8. Two affected siblings in this family exhibit global developmental delay and intellectual disability as shared characteristic features of MRT71 syndrome, and we further characterize their observed dysmorphic features and brain MRI findings. This description of a third family with a truncating ALKBH8 variant from a distinct population broadens the phenotypic and genotypic spectrum of MRT71 syndrome, affirms that perturbations in tRNA biogenesis can contribute to neurogenetic disease traits, and firmly establishes ALKBH8 as a novel neurodevelopmental disease gene.
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http://dx.doi.org/10.1002/ajmg.a.62100DOI Listing
April 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 Feb 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome.

Am J Hum Genet 2021 02;108(2):337-345

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896104PMC
February 2021

Germline Cancer-Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report from the Children's Oncology Group.

J Natl Cancer Inst 2020 Dec 29. Epub 2020 Dec 29.

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.

Background: Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignancy.

Methods: We performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented through the Children's Oncology Group. We compared the prevalence of cancer-predisposition variants in 63 autosomal dominant cancer-predisposition genes in these patients with population controls (n = 9,963). All statistical tests were two-sided.

Results: We identified germline cancer-predisposition variants in 45 RMS patients (7.3%; all FOXO1 fusion-negative) across 15 autosomal dominant genes, which was statistically significantly enriched compared with controls (1.4%; p = 1.3 × 10-22). Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric RMS risk, such as Li-Fraumeni syndrome (TP53) and neurofibromatosis type I (NF1). Notably, five patients had well-described oncogenic missense variants in HRAS (p.G12V and p. G12S) associated with Costello syndrome. Also, genetic etiology differed with histology, as germline variants were more frequent in embryonal versus alveolar RMS patients (10.0% vs. 3.0%, p = .02). While patients with a cancer-predisposition variant tended to be younger at diagnosis (p = 9.9 × 10-4), 40.0% of germline variants were identified in those >3 years of age, which is in contrast to current genetic testing recommendations based on early age at diagnosis.

Conclusions: These findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer-susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.
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http://dx.doi.org/10.1093/jnci/djaa204DOI Listing
December 2020

Parliament2: Accurate structural variant calling at scale.

Gigascience 2020 12;9(12)

Human Genome Sequencing Center, One Baylor Plaza, Baylor College of Medicine, Houston, TX 77030, USA.

Background: Structural variants (SVs) are critical contributors to genetic diversity and genomic disease. To predict the phenotypic impact of SVs, there is a need for better estimates of both the occurrence and frequency of SVs, preferably from large, ethnically diverse cohorts. Thus, the current standard approach requires the use of short paired-end reads, which remain challenging to detect, especially at the scale of hundreds to thousands of samples.

Findings: We present Parliament2, a consensus SV framework that leverages multiple best-in-class methods to identify high-quality SVs from short-read DNA sequence data at scale. Parliament2 incorporates pre-installed SV callers that are optimized for efficient execution in parallel to reduce the overall runtime and costs. We demonstrate the accuracy of Parliament2 when applied to data from NovaSeq and HiSeq X platforms with the Genome in a Bottle (GIAB) SV call set across all size classes. The reported quality score per SV is calibrated across different SV types and size classes. Parliament2 has the highest F1 score (74.27%) measured across the independent gold standard from GIAB. We illustrate the compute performance by processing all 1000 Genomes samples (2,691 samples) in <1 day on GRCH38. Parliament2 improves the runtime performance of individual methods and is open source (https://github.com/slzarate/parliament2), and a Docker image, as well as a WDL implementation, is available.

Conclusion: Parliament2 provides both a highly accurate single-sample SV call set from short-read DNA sequence data and enables cost-efficient application over cloud or cluster environments, processing thousands of samples.
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http://dx.doi.org/10.1093/gigascience/giaa145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751401PMC
December 2020

Oligonucleotide Capture Sequencing of the SARS-CoV-2 Genome and Subgenomic Fragments from COVID-19 Individuals.

bioRxiv 2020 Dec 11. Epub 2020 Dec 11.

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity and provided evidence of expression of ORF10. Heterogeneous allelic frequencies along the 20kb ORF1ab gene suggested the presence of a defective interfering viral RNA species subpopulation in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.
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http://dx.doi.org/10.1101/2020.12.11.421057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743067PMC
December 2020

Primate phylogenomics uncovers multiple rapid radiations and ancient interspecific introgression.

PLoS Biol 2020 12 3;18(12):e3000954. Epub 2020 Dec 3.

Department of Biology and Department of Computer Science, Indiana University, Bloomington, Indiana, United States of America.

Our understanding of the evolutionary history of primates is undergoing continual revision due to ongoing genome sequencing efforts. Bolstered by growing fossil evidence, these data have led to increased acceptance of once controversial hypotheses regarding phylogenetic relationships, hybridization and introgression, and the biogeographical history of primate groups. Among these findings is a pattern of recent introgression between species within all major primate groups examined to date, though little is known about introgression deeper in time. To address this and other phylogenetic questions, here, we present new reference genome assemblies for 3 Old World monkey (OWM) species: Colobus angolensis ssp. palliatus (the black and white colobus), Macaca nemestrina (southern pig-tailed macaque), and Mandrillus leucophaeus (the drill). We combine these data with 23 additional primate genomes to estimate both the species tree and individual gene trees using thousands of loci. While our species tree is largely consistent with previous phylogenetic hypotheses, the gene trees reveal high levels of genealogical discordance associated with multiple primate radiations. We use strongly asymmetric patterns of gene tree discordance around specific branches to identify multiple instances of introgression between ancestral primate lineages. In addition, we exploit recent fossil evidence to perform fossil-calibrated molecular dating analyses across the tree. Taken together, our genome-wide data help to resolve multiple contentious sets of relationships among primates, while also providing insight into the biological processes and technical artifacts that led to the disagreements in the first place.
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http://dx.doi.org/10.1371/journal.pbio.3000954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738166PMC
December 2020

PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia.

Nat Commun 2020 11 19;11(1):5903. Epub 2020 Nov 19.

Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.

The neuronal primary cilium and centriolar satellites have functions in neurogenesis, but little is known about their roles in the postnatal brain. We show that ablation of pericentriolar material 1 in the mouse leads to progressive ciliary, anatomical, psychomotor, and cognitive abnormalities. RNAseq reveals changes in amine- and G-protein coupled receptor pathways. The physiological relevance of this phenotype is supported by decreased available dopamine D2 receptor (D2R) levels and the failure of antipsychotic drugs to rescue adult behavioral defects. Immunoprecipitations show an association with Pcm1 and D2Rs. Finally, we sequence PCM1 in two human cohorts with severe schizophrenia. Systematic modeling of all discovered rare alleles by zebrafish in vivo complementation reveals an enrichment for pathogenic alleles. Our data emphasize a role for the pericentriolar material in the postnatal brain, with progressive degenerative ciliary and behavioral phenotypes; and they support a contributory role for PCM1 in some individuals diagnosed with schizophrenia.
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http://dx.doi.org/10.1038/s41467-020-19637-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677393PMC
November 2020

Sequence analysis in reveals pervasiveness of X-Y arms races in mammalian lineages.

Genome Res 2020 12 18;30(12):1716-1726. Epub 2020 Nov 18.

Whitehead Institute, Cambridge, Massachusetts 02142, USA.

Studies of Y Chromosome evolution have focused primarily on gene decay, a consequence of suppression of crossing-over with the X Chromosome. Here, we provide evidence that suppression of X-Y crossing-over unleashed a second dynamic: selfish X-Y arms races that reshaped the sex chromosomes in mammals as different as cattle, mice, and men. Using super-resolution sequencing, we explore the Y Chromosome of (bull) and find it to be dominated by massive, lineage-specific amplification of testis-expressed gene families, making it the most gene-dense Y Chromosome sequenced to date. As in mice, an X-linked homolog of a bull Y-amplified gene has become testis-specific and amplified. This evolutionary convergence implies that lineage-specific X-Y coevolution through gene amplification, and the selfish forces underlying this phenomenon, were dominatingly powerful among diverse mammalian lineages. Together with Y gene decay, X-Y arms races molded mammalian sex chromosomes and influenced the course of mammalian evolution.
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http://dx.doi.org/10.1101/gr.269902.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706723PMC
December 2020

High-depth African genomes inform human migration and health.

Nature 2020 10 28;586(7831):741-748. Epub 2020 Oct 28.

Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.
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http://dx.doi.org/10.1038/s41586-020-2859-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759466PMC
October 2020

NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity.

Hum Mol Genet 2021 01;29(21):3516-3531

Regeneron Genetics Center, Tarrytown, NY 10591, USA.

Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.
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http://dx.doi.org/10.1093/hmg/ddaa237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788287PMC
January 2021

Genome-enabled insights into the biology of thrips as crop pests.

BMC Biol 2020 10 19;18(1):142. Epub 2020 Oct 19.

Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, St. Lucia, QLD, 4072, Australia.

Background: The western flower thrips, Frankliniella occidentalis (Pergande), is a globally invasive pest and plant virus vector on a wide array of food, fiber, and ornamental crops. The underlying genetic mechanisms of the processes governing thrips pest and vector biology, feeding behaviors, ecology, and insecticide resistance are largely unknown. To address this gap, we present the F. occidentalis draft genome assembly and official gene set.

Results: We report on the first genome sequence for any member of the insect order Thysanoptera. Benchmarking Universal Single-Copy Ortholog (BUSCO) assessments of the genome assembly (size = 415.8 Mb, scaffold N50 = 948.9 kb) revealed a relatively complete and well-annotated assembly in comparison to other insect genomes. The genome is unusually GC-rich (50%) compared to other insect genomes to date. The official gene set (OGS v1.0) contains 16,859 genes, of which ~ 10% were manually verified and corrected by our consortium. We focused on manual annotation, phylogenetic, and expression evidence analyses for gene sets centered on primary themes in the life histories and activities of plant-colonizing insects. Highlights include the following: (1) divergent clades and large expansions in genes associated with environmental sensing (chemosensory receptors) and detoxification (CYP4, CYP6, and CCE enzymes) of substances encountered in agricultural environments; (2) a comprehensive set of salivary gland genes supported by enriched expression; (3) apparent absence of members of the IMD innate immune defense pathway; and (4) developmental- and sex-specific expression analyses of genes associated with progression from larvae to adulthood through neometaboly, a distinct form of maturation differing from either incomplete or complete metamorphosis in the Insecta.

Conclusions: Analysis of the F. occidentalis genome offers insights into the polyphagous behavior of this insect pest that finds, colonizes, and survives on a widely diverse array of plants. The genomic resources presented here enable a more complete analysis of insect evolution and biology, providing a missing taxon for contemporary insect genomics-based analyses. Our study also offers a genomic benchmark for molecular and evolutionary investigations of other Thysanoptera species.
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http://dx.doi.org/10.1186/s12915-020-00862-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570057PMC
October 2020

Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome.

Am J Med Genet A 2020 Oct 13. Epub 2020 Oct 13.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Robinow syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A underlying the etiology of RS. The aforementioned "Robinow-associated genes" and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene-targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1, ROR2, and NXN. One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN, which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS.
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http://dx.doi.org/10.1002/ajmg.a.61908DOI Listing
October 2020

NF-κB and STAT3 co-operation enhances high glucose induced aggressiveness of cholangiocarcinoma cells.

Life Sci 2020 Dec 7;262:118548. Epub 2020 Oct 7.

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.

Aims: The present report aimed to investigate the underlying genes and pathways of high glucose driving cholangiocarcinoma (CCA) aggressiveness.

Main Methods: We screened and compared the gene expression profiles obtained by RNA sequencing, of CCA cells cultured in high and normal glucose. Results from the transcriptomic analysis were confirmed in additional cell lines using in vitro migration-invasion assay, Western blotting and immunocytofluorescence.

Key Findings: Data indicated that high glucose increased the expression of interleukin-1β (IL-1β), an upstream regulator of nuclear factor-κB (NF-κB) pathway, through the nuclear localization of NF-κB. High glucose-induced NF-κB increased the migration and invasion of CCA cells and the expression of downstream NF-κB targeted genes associated with aggressiveness, including interleukin-6, a potent triggering signal of the signal transducer and activator of transcription 3 (STAT3) pathway. Such effects were reversed by inhibiting NF-κB nuclear translocation which additionally reduced the phosphorylation of STAT3 at Y705.

Significance: These results indicate that NF-κB is activated by high glucose and they suggest that NF-κB interaction with STAT3 enhances CCA aggressiveness. Therefore, targeting multiple pathways such as STAT3 and NF-κB might improve CCA treatment outcome especially in condition such as hyperglycemia.
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http://dx.doi.org/10.1016/j.lfs.2020.118548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686287PMC
December 2020

Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.

Hum Mutat 2020 12 8;41(12):2094-2104. Epub 2020 Oct 8.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.
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http://dx.doi.org/10.1002/humu.24118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903881PMC
December 2020

Human NK cell deficiency as a result of biallelic mutations in MCM10.

J Clin Invest 2020 10;130(10):5272-5286

Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA.

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.
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http://dx.doi.org/10.1172/JCI134966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524476PMC
October 2020