Scientific Publications

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313 Results

2023

Genome sequencing detects a wide range of clinically relevant copy number variants and other genomic alterations

James KN, Chowdhury S, Ding Y, Batalov S, Watkins K, Kwon YH, Van Der Kraan L, Ellsworth K, Kingsmore SF, Guidugli L. 

Genet Med. 2023 Oct 20:101006. doi: 10.1016/j.gim.2023.101006. Online ahead of print. ABSTRACT PURPOSE: Copy number variants (CNVs) and other non-SNV/indel variant types contribute an important proportion of diagnoses in individuals with suspected genetic disease. This study describes the range of such variants detected by genome sequencing (GS). METHODS: For a pediatric cohort of 1032 participants undergoing clinical GS, we characterize the CNVs and other non-SNV/indel variant types that were reported, including aneuploidies, mobile element insertions, and uniparental disomies, and we describe the bioinformatic pipeline used to detect these variants. RESULTS: Together, these genetic alterations accounted for 15.8% of reported variants. Notably, 67.9% of these were deletions, 32.9% of which overlapped a single gene, and many deletions were reported together with a second variant in the same gene in cases of recessive disease. A retrospective medical record review in a subset of this cohort revealed that up to six additional genetic tests were ordered in 68% (26/38) of cases, some of which failed to report the CNVs/rare variants reported on GS. CONCLUSION: GS detected a broad range of reported variant types, including CNVs ranging in size from 1 Kb to 46 Mb. PMID:37869996 DOI:10.1016/j.gim.2023.101006

October 20, 2023
RPM for NICU and PICU

Cell-type-resolved somatic mosaicism reveals clonal dynamics of the human forebrain

Chung C, Yang X, Hevner RF, Kennedy K, Vong KI, Liu Y, Patel A, Nedunuri R, Barton ST, Barrows C, Stanley V, Mittal S, Breuss MW, Schlachetzki JCM, Gleeson JG.

bioRxiv. 2023 Oct 26:2023.10.24.563814. doi: 10.1101/2023.10.24.563814. Preprint. ABSTRACT Debate remains around anatomic origins of specific brain cell subtypes and lineage relationships within the human forebrain. Thus, direct observation in the mature human brain is critical for a complete understanding of the structural organization and cellular origins. Here, we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific Mosaic Variant Barcode Analysis. From four hemispheres from two different human neurotypical donors, we identified 287 and 780 mosaic variants (MVs), respectively that were used to deconvolve clonal dynamics. Clonal spread and allelic fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted compared with resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome-transcriptome analysis at both a cell-type-specific and single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1 + inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of MVs across 17 locations within one parietal lobe reveals restrictions of clonal spread in the anterior-posterior axis precedes that of the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus cell-type resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain. PMID:37961480 | PMC:PMC10634852 | DOI:10.1101/2023.10.24.563814

October 15, 2023
Neurogenomics

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Kaiyrzhanov R, Rad A, Lin SJ, Bertoli-Avella A, Kallemeijn WW, Godwin A, Zaki MS, Huang K, Lau T, Petree C, Efthymiou S, Ghayoor Karimiani E, Hempel M, Normand EA, Rudnik-Schöneborn S, Schatz UA, Baggelaar MP, Ilyas M, Sultan T, Alvi JR, Ganieva M, Fowler B, Aanicai R, Akay Tayfun G, Al Saman A, Alswaid A, Amiri N, Asilova N, Shotelersuk V, Yeetong P, Azam M, Babaei M, Bahrami Monajemi G, Mohammadi P, Samie S, Banu SH, Basto JP, Kortüm F, Bauer M, Bauer P, Beetz C, Garshasbi M, Hameed Issa A, Eyaid W, Ahmed H, Hashemi N, Hassanpour K, Herman I, Ibrohimov S, Abdul-Majeed BA, Imdad M, Isrofilov M, Kaiyal Q, Khan S, Kirmse B, Koster J, Lourenço CM, Mitani T, Moldovan O, Murphy D, Najafi M, Pehlivan D, Rocha ME, Salpietro V, Schmidts M, Shalata A, Mahroum M, Talbeya JK, Taylor RW, Vazquez D, Vetro A, Waterham HR, Zaman M, Schrader TA, Chung WK, Guerrini R, Lupski JR, Gleeson J, Suri M, Jamshidi Y, Bhatia KP, Vona B, Schrader M, Severino M, Guille M, Tate EW, Varshney GK, Houlden H, Maroofian R.

Brain. 2023 Nov 10:awad380. doi: 10.1093/brain/awad380. Online ahead of print. ABSTRACT The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders. PMID:37951597 | DOI:10.1093/brain/awad380

October 13, 2023
Neurogenomics

Biallelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome

Engal E, Oja KT, Maroofian R, Geminder O, Le TL, Marzin P, Guimier A, Mor E, Zvi N, Elefant N, Zaki MS, Gleeson JG, Muru K, Pajusalu S, Wojcik MH, Pachat D, Elmaksoud MA, Chan Jeong W, Lee H, Bauer P, Zifarelli G, Houlden H, Daana M, Elpeleg O, Amiel J, Lyonnet S, Gordon CT, Harel T, Õunap K, Salton M, Mor-Shaked H.

Am J Hum Genet. 2023 Nov 7:S0002-9297(23)00366-X. doi: 10.1016/j.ajhg.2023.10.013. Online ahead of print. ABSTRACT Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WW domain-binding protein 4 (WBP4) is part of the early spliceosomal complex and has not been previously associated with human pathologies in the Online Mendelian Inheritance in Man (OMIM) database. Through GeneMatcher, we identified ten individuals from eight families with a severe neurodevelopmental syndrome featuring variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal, and gastrointestinal abnormalities. Genetic analysis revealed five different homozygous loss-of-function variants in WBP4. Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated a complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including in genes associated with abnormalities of the nervous system, potentially underlying the phenotypes of the probands. We conclude that biallelic variants in WBP4 cause a developmental disorder with variable presentations, adding to the growing list of human spliceosomopathies. PMID:37963460 | DOI:10.1016/j.ajhg.2023.10.013

October 13, 2023
Neurogenomics

A genetics-guided approach to the clinical management of schizophrenia

Besterman AD. 

Schizophr Res. 2023 Oct 7:S0920-9964(23)00353-5. doi: 10.1016/j.schres.2023.09.042. Online ahead of print. ABSTRACT Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of populations across cultures. There have been recent major advancements in our understanding of the genetic architecture of schizophrenia. Both rare, highly penetrant genetic variants as well as common, low-penetrant genetic variants can predispose individuals to schizophrenia and can impact the way people metabolize psychoactive medications used to treat schizophrenia. However, the impact of these findings on the clinical management of schizophrenia remains limited. This review highlights the few places where genetics currently informs schizophrenia management strategies, discusses major limitations, and reviews promising areas of genetics research that are most likely to impact future schizophrenia care. Specifically, I focuss on psychiatric genetic counseling, genetic testing strategies, pharmacogenetics, polygenic risk, and genetics-guided treatment. Lastly, I emphasize important ethical considerations in the clinical use of genetics for schizophrenia management, including the exacerbation of healthcare inequalities and unintended consequences of new genetic technologies. PMID:37813777 DOI:10.1016/j.schres.2023.09.042

October 7, 2023

Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease

Lemire G, Sanchis-Juan A, Russell K, Baxter S, Chao KR, Singer-Berk M, Groopman E, Wong I, England E, Goodrich J, Pais L, Austin-Tse C, DiTroia S, O’Heir E, Ganesh VS, Wojcik MH, Evangelista E, Snow H, Osei-Owusu I, Fu J, Singh M, Mostovoy Y, Huang S, Garimella K, Kirkham SL, Neil JE, Shao DD, Walsh CA, Argili E, Le C, Sherr EH, Gleeson J, Shril S, Schneider R, Hildebrandt F, Sankaran VG, Madden JA, Genetti CA, Beggs AH, Agrawal PB, Bujakowska KM, Place E, Pierce EA, Donkervoort S, Bönnemann CG, Gallacher L, Stark Z, Tan T, White SM, Töpf A, Straub V, Fleming MD, Pollak MR, Õunap K, Pajusalu S, Donald KA, Bruwer Z, Ravenscroft G, Laing NG, MacArthur DG, Rehm HL, Talkowski ME, Brand H, O’Donnell-Luria A.

medRxiv. 2023 Oct 5:2023.10.05.23296595. doi: 10.1101/2023.10.05.23296595. Preprint. ABSTRACT Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium. Each family’s CNV data was analyzed using the seqr platform and candidate CNVs classified using the 2020 ACMG/ClinGen CNV interpretation standards. We developed additional evidence criteria to address situations not covered by the current standards. The addition of CNV calling to exome analysis identified causal CNVs for 173 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb with estimates that 44% would not have been detected by standard chromosomal microarrays. The causal CNVs consisted of 141 deletions, 15 duplications, 4 suspected complex structural variants (SVs), 3 insertions and 10 complex SVs, the latter two groups being identified by orthogonal validation methods. We interpreted 153 CNVs as likely pathogenic/pathogenic and 20 CNVs as high interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs. PMID:37873196 DOI:10.1101/2023.10.05.23296595

October 5, 2023
Neurogenomics

The Promise and Perils of Next-Generation DNA Sequencing at Birth: Proceedings of a Workshop–in Brief

National Academies of Sciences, Engineering, and Medicine. 2023. The Promise and Perils of Next-Generation DNA Sequencing at Birth: Proceedings of a Workshop–in Brief. Washington, DC: The National Academies Press. https://doi.org/10.17226/2724 Pilot programs are employing whole genome sequencing and whole exome sequencing during the newborn phase both within the United States and internationally. While sequencing offers the opportunity to screen for treatable but not clinically evident conditions early in a child’s life, it raises a host of ethical, legal, and social questions for experts, including parents, to consider. The National Academies Roundtable on Genomics and Precision Health hosted experts from health care, industry, academia, the federal and state governments, and patient and consumer advocacy groups for a June 2023 workshop. Participants, including RCIGM investigator Nathaly Sweeney, explored the potential benefits and harms, data security, and health equity considerations for the widespread utilization of newborn genome sequencing in the U.S. This publication summarizes the presentation and discussion of the workshop.

September 29, 2023
Newborn Screening

An approach for collaborative development of a federated biomedical knowledge graph-based question-answering system: Question-of-the-Month challenges

Fecho K, Bizon C, Issabekova T, Moxon S, Thessen AE, Abdollahi S, Baranzini SE, Belhu B, Byrd WE, Chung L, Crouse A, Duby MP, Ferguson S, Foksinska A, Forero L, Friedman J, Gardner V, Glusman G, Hadlock J, Hanspers K, Hinderer E, Hobbs C, Hyde G, Huang S, Koslicki D, Mease P, Muller S, Mungall CJ, Ramsey SA, Roach J, Rubin I, Schurman SH, Shalev A, Smith B, Soman K, Stemann S, Su AI, Ta C, Watkins PB, Williams MD, Wu C, Xu CH; Biomedical Data Translator Consortium.

J Clin Transl Sci. 2023 Sep 14;7(1):e214. doi: 10.1017/cts.2023.619. eCollection 2023. ABSTRACT Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium, we have developed a knowledge graph-based question-answering system designed to augment human reasoning and accelerate translational scientific discovery: the Translator system. We have applied the Translator system to answer biomedical questions in the context of a broad array of diseases and syndromes, including Fanconi anemia, primary ciliary dyskinesia, multiple sclerosis, and others. A variety of collaborative approaches have been used to research and develop the Translator system. One recent approach involved the establishment of a monthly “Question-of-the-Month (QotM) Challenge” series. Herein, we describe the structure of the QotM Challenge; the six challenges that have been conducted to date on drug-induced liver injury, cannabidiol toxicity, coronavirus infection, diabetes, psoriatic arthritis, and ATP1A3-related phenotypes; the scientific insights that have been gleaned during the challenges; and the technical issues that were identified over the course of the challenges and that can now be addressed to foster further development of the prototype Translator system. We close with a discussion on Large Language Models such as ChatGPT and highlight differences between those models and the Translator system. PMID:37900350 | PMC:PMC10603356 | DOI:10.1017/cts.2023.619

September 14, 2023

Unique Challenges of NIPT for Sex Chromosome Aneuploidy

Wilkins-Haug L, Reimers R.

Clin Obstet Gynecol. 2023 Sep 1;66(3):568-578. doi: 10.1097/GRF.0000000000000804. Epub 2023 Jul 24. ABSTRACT Noninvasive prenatal testing (NIPT) for the sex chromosome aneuploidies (45,X, 47,XXY, 47,XXX, and 47,XYY) differs significantly from that for the autosomal aneuploidies (trisomy 13, 18, and 21). As a group, sex chromosome aneuploidies occur more commonly (1/400) than any one isolated autosomal aneuploidy, the phenotypic variation is greater, the role of mosaicism more challenging, and the positive predictive value of a high-risk NIPT result is substantially lower. These considerations should be identified during pretest counseling, the inclusion of sex chromosome testing offered separately, and the differences from autosomal aneuploidy NIPT clearly delineated. PMID:37650669 DOI:10.1097/GRF.0000000000000804

September 1, 2023
Prenatal Screening

Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome

Beaman MM, Guidugli L, Hammer M, Barrows C, Gregor A, Lee S, Deak KL, McDonald MT, Jensen C, Zaki MS, Masri AT, Hobbs CA, Gleeson JG, Cohen JL.

Am J Med Genet A. 2023 Aug 19. doi: 10.1002/ajmg.a.63363. Online ahead of print. ABSTRACT Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease. PMID:37596828 DOI:10.1002/ajmg.a.63363

August 19, 2023
Neurogenomics

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