Scientific Publications

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322 Results

2021

Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity

Besterman AD, Althoff T, Elfferich P, Gutierrez-Mejia I, Sadik J, Bernstein JA, van Ierland Y, Kattentidt-Mouravieva AA, Nellist M, Abramson J, Martinez-Agosto JA.

PLoS Genet. 2021 Jul 1;17(7):e1009651. doi: 10.1371/journal.pgen.1009651. Online ahead of print. ABSTRACT Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder characterized by macrocephaly/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures. It is caused by dominant missense mutations in MTOR. The pathogenicity of novel variants in MTOR in patients with neurodevelopmental disorders can be difficult to determine and the mechanism by which variants cause disease remains poorly understood. We report 7 patients with SKS with 4 novel MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR activation and interrogate disease mechanisms. We complete structural analyses to understand the 3D properties of pathogenic variants. We examine the accuracy of relative accessible surface area, a quantitative measure of amino acid side-chain accessibility, as a predictor of MTOR variant pathogenicity. We describe novel clinical features of patients with SKS. We confirm MTOR Complex 1 activation and identify MTOR Complex 2 activation as a new potential mechanism of disease in SKS. We find that pathogenic MTOR variants disproportionately cluster in hotspots in the core of the protein, where they disrupt alpha helix packing due to the insertion of bulky amino acid side chains. We find that relative accessible surface area is significantly lower for SKS-associated variants compared to benign variants. We expand the phenotype of SKS and demonstrate that additional pathways of activation may contribute to disease. Incorporating 3D properties of MTOR variants may help in pathogenicity classification. We hope these findings may contribute to improving the precision of care and therapeutic development for individuals with SKS. PMID:34197453 | DOI:10.1371/journal.pgen.1009651

July 9, 2021
Gene Discovery

Uncertain, Not Unimportant: Callosal Dysgenesis and Variants of Uncertain Significance in ROBO1

Woodring TS, Mirza MH, Benavides V, Ellsworth KA, Wright MS, Javed MJ, Ramiro S.

Pediatrics. 2021 Jun 30:e2020019000. doi: 10.1542/peds.2020-019000. Online ahead of print. ABSTRACT Congenital anomalies affect 3% to 5% of births and remain the leading cause of infant death in the United States. As whole exome and genome sequencing are increasingly used to diagnose underlying genetic disease, the patient’s clinical presentation remains the most important context for interpreting sequencing results, including frequently reported variants of uncertain significance (VUS). Classification of a variant as VUS acknowledges limits on evidence to establish whether a variant can be classified as pathogenic or benign according to the American College of Medical Genetics guidelines. Importantly, the VUS designation reflects limits on the breadth of evidence linking the genetic variant to a disease. However, available evidence, although limited, may be surprisingly relevant in an individual patient’s case. Accordingly, a VUS result should be approached neither as nondiagnostic genetic result nor as automatically “uncertain” in its potential to guide clinical decision-making. In this article, we discuss a case of an infant born at 29 weeks 4 days without a corpus callosum, whose whole genome sequencing yielded compound heterozygous variants both classified as VUS in ROBO1, a gene encoding for a receptor involved in a canonical signaling mechanism that guides axons across midline. Approaching the VUS result as potentially pathogenic, we found the infant ultimately had pituitary dysfunction and renal anomalies consistent with other reported ROBO1 variants and basic science literature. Accordingly, we highlight resources for variant interpretation available to clinicians to evaluate VUS results, particularly as they inform the diagnosis of individually rare but collectively common rare diseases. PMID:34193621 | DOI:10.1542/peds.2020-019000

June 30, 2021
Infant Mortality

Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish

Lin SJ, Vona B, Barbalho PG, Kaiyrzhanov R, Maroofian R, Petree C, Severino M, Stanley V, Varshney P, Bahena P, Alzahrani F, Alhashem A, Pagnamenta AT, Aubertin G, Estrada-Veras JI, Hernández HAD, Mazaheri N, Oza A, Thies J, Renaud DL, Dugad S, McEvoy J, Sultan T, Pais LS, Tabarki B, Villalobos-Ramirez D, Rad A; Genomics England Research Consortium, Galehdari H, Ashrafzadeh F, Sahebzamani A, Saeidi K, Torti E, Elloumi HZ, Mora S, Palculict TB, Yang H, Wren JD, Ben Fowler, Joshi M, Behra M, Burgess SM, Nath SK, Hanna MG, Kenna M, Merritt JL 2nd, Houlden H, Karimiani EG, Zaki MS, Haaf T, Alkuraya FS, Gleeson JG, Varshney GK.

Genet Med. 2021 Jun 25. doi: 10.1038/s41436-021-01239-1. Online ahead of print. ABSTRACT PURPOSE: Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo. METHODS: Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish. RESULTS: We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1-/- knockouts. CONCLUSION: Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets. PMID:34172899 | DOI:10.1038/s41436-021-01239-1

June 25, 2021
Neurogenomics

Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features

Zaki MS, Accogli A, Mirzaa G, Rahman F, Mohammed H, Porras-Hurtado GL, Efthymiou S, Maqbool S, Shukla A, Vincent JB, Hussain A, Mir A, Beetz C, Leubauer A, Houlden H, Gleeson JG, Maroofian R.

Eur J Hum Genet. 2021 Jun 24. doi: 10.1038/s41431-021-00910-0. Online ahead of print. ABSTRACT The PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outline the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior. PMID:34163010 | DOI:10.1038/s41431-021-00910-0

June 24, 2021
Neurogenomics

Sperm mosaicism: implications for genomic diversity and disease

Breuss MW, Yang X, Gleeson JG. 

Trends Genet. 2021 Jun 19:S0168-9525(21)00139-6. doi: 10.1016/j.tig.2021.05.007. Online ahead of print. ABSTRACT While sperm mosaicism has few consequences for men, the offspring and future generations are unwitting recipients of gonadal cell mutations, often yielding severe disease. Recent studies, fueled by emergent technologies, show that sperm mosaicism is a common source of de novo mutations (DNMs) that underlie severe pediatric disease as well as human genetic diversity. Sperm mosaicism can be divided into three types: Type I arises during sperm meiosis and is non-age dependent; Type II arises in spermatogonia and increases as men age; and Type III arises during paternal embryogenesis, spreads throughout the body, and contributes stably to sperm throughout life. Where Types I and II confer little risk of recurrence, Type III may confer identifiable risk to future offspring. These mutations are likely to be the single largest contributor to human genetic diversity. New sequencing approaches may leverage this framework to evaluate and reduce disease risk for future generations. PMID:34158173 | DOI:10.1016/j.tig.2021.05.007

June 19, 2021
Neurogenomics

Postmortem whole-genome sequencing on a dried blood spot identifies a novel homozygous SUOX variant causing isolated sulfite oxidase deficiency

Owen MJ, Lenberg J, Feigenbaum A, Gold J, Chau K, Bezares-Orin Z, Ding Y, Chowdhury S, Kingsmore SF. 

Cold Spring Harb Mol Case Stud. 2021 Jun 11;7(3):a006091. doi: 10.1101/mcs.a006091. Print 2021 Jun. ABSTRACT Rapid whole-genome sequencing (rWGS) has shown that genetic diseases are a common cause of infant mortality in neonatal intensive care units. Dried blood spots collected for newborn screening allow investigation of causes of infant mortality that were not diagnosed during life. Here, we present a neonate who developed seizures and encephalopathy on the third day of life that was refractory to antiepileptic medications. The patient died on day of life 16 after progressive respiratory failure and sepsis. The parents had lost two prior children after similar presentations, neither of whom had a definitive diagnosis. Postmortem rWGS of a dried blood spot identified a pathogenic homozygous frameshift variant in the SUOX gene associated with isolated sulfite oxidase deficiency (c.1390_1391del, p.Leu464GlyfsTer10). This case highlights that early, accurate molecular diagnosis has the potential to influence prenatal counseling and guide management in rare, genetic disorders and has added importance in cases of a strong family history and risk factors such as consanguinity. PMID:34117075 | DOI:10.1101/mcs.a006091

June 14, 2021
Infant MortalityrWGS

Mapping methylation quantitative trait loci in cardiac tissues nominates risk loci and biological pathways in congenital heart disease

Li M, Lyu C, Huang M, Do C, Tycko B, Lupo PJ, MacLeod SL, Randolph CE, Liu N, Witte JS, Hobbs CA.

BMC Genom Data. 2021 Jun 10;22(1):20. doi: 10.1186/s12863-021-00975-2. ABSTRACT BACKGROUND: Most congenital heart defects (CHDs) result from complex interactions among genetic susceptibilities, epigenetic modifications, and maternal environmental exposures. Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation will enhance our understanding of pathogenesis in this important type of congenital disorder. We investigated cis-acting effects of genetic single nucleotide polymorphisms (SNPs) on local DNA methylation patterns within 83 cardiac tissue samples and prioritized their contributions to CHD risk by leveraging results of CHD genome-wide association studies (GWAS) and their effects on cardiac gene expression. RESULTS: We identified 13,901 potential methylation quantitative trait loci (mQTLs) with a false discovery threshold of 5%. Further co-localization analyses and Mendelian randomization indicated that genetic variants near the HLA-DRB6 gene on chromosome 6 may contribute to CHD risk by regulating the methylation status of nearby CpG sites. Additional SNPs in genomic regions on chromosome 10 (TNKS2-AS1 gene) and chromosome 14 (LINC01629 gene) may simultaneously influence epigenetic and transcriptomic variations within cardiac tissues. CONCLUSIONS: Our results support the hypothesis that genetic variants may influence the risk of CHDs through regulating the changes of DNA methylation and gene expression. Our results can serve as an important source of information that can be integrated with other genetic studies of heart diseases, especially CHDs. PMID:34112112 | DOI:10.1186/s12863-021-00975-2

June 10, 2021

Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children’s hospitals demonstrates improved clinical outcomes and reduced costs of care

Dimmock D, Caylor S, Waldman B, Benson W, Ashburner C, Carmichael JL, Carroll J, Cham E, Chowdhury S, Cleary J, D’Harlingue A, Doshi A, Ellsworth K, Galarreta CI, Hobbs C, Houtchens K, Hunt J, Joe P, Joseph M, Kaplan RH, Kingsmore SF, Knight J, Kochhar A, Kronick RG, Limon J, Martin M, Rauen KA, Schwarz A, Shankar SP, Spicer R, Rojas MA, Vargas-Shiraishi O, Wigby K, Zadeh N, Farnaes L. 

Am J Hum Genet. 2021 May 29:S0002-9297(21)00192-0. doi: 10.1016/j.ajhg.2021.05.008. Online ahead of print. ABSTRACT Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children’s hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear. PMID:34089648 | DOI:10.1016/j.ajhg.2021.05.008

June 7, 2021
RPM for NICU and PICUrWGSrWGS Efficacy

Rapid Sequencing-Based Diagnosis of Thiamine Metabolism Dysfunction Syndrome

Owen MJ, Niemi AK, Dimmock DP, Speziale M, Nespeca M, Chau KK, Van Der Kraan L, Wright MS, Hansen C, Veeraraghavan N, Ding Y, Lenberg J, Chowdhury S, Hobbs CA, Batalov S, Zhu Z, Nahas SA, Gilmer S, Knight G, Lefebvre S, Reynders J, Defay T, Weir J, Thomson VS, Fraser L, Lajoie BR, McPhail TK, Mehtalia SS, Kunard CM, Hall KP, Kingsmore SF.

N Engl J Med. 2021 Jun 3;384(22):2159-2161. doi: 10.1056/NEJMc2100365. NO ABSTRACT PMID:34077649 | DOI:10.1056/NEJMc2100365

June 3, 2021
rWGS

Ending a diagnostic odyssey: Moving from exome to genome to identify cockayne syndrome

Friedman J, Bird LM, Haas R, Robbins SL, Nahas SA, Dimmock DP, Yousefzadeh MJ, Witt MA, Niedernhofer LJ, Chowdhury S. 

Mol Genet Genomic Med. 2021 Jun 2:e1623. doi: 10.1002/mgg3.1623. Online ahead of print. ABSTRACT BACKGROUND: Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross-complementation group 6 (ERCC6 OMIM: *609413) is the gene most frequently mutated in CS. METHODS: A child with pre and postnatal growth failure and progressive neurologic deterioration with multisystem involvement, and with nondiagnostic whole-exome sequencing, was screened for causal variants with whole-genome sequencing (WGS). RESULTS: WGS identified biallelic ERCC6 variants, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of ERCC6 mRNA and protein expression, normal unscheduled DNA synthesis, and impaired recovery of RNA synthesis in patient fibroblasts following UV-irradiation. CONCLUSION: The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify noncoding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing. PMID:34076366 | DOI:10.1002/mgg3.1623

June 2, 2021
Genetic Neurologic DiseaseRare Disease

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