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.
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
Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases
Rossignol F, Duarte Moreno MS, Benoist JF, Boehm M, Bourrat E, Cano A, Chabrol B, Cosson C, Díaz JLD, D’Harlingue A, Dimmock D, Freeman AF, García MT, Garganta C, Goerge T, Halbach SS, de Laffolie J, Lam CT, Martin L, Martins E, Meinhardt A, Melki I, Ombrello AK, Pérez N, Quelhas D, Scott A, Slavotinek AM, Soares AR, Stein SL, Süßmuth K, Thies J, Ferreira CR, Schiff M.
Genet Med. 2021 May 26. doi: 10.1038/s41436-021-01200-2. Online ahead of print.
ABSTRACT
PURPOSE: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature.
METHODS: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival.
RESULTS: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old.
CONCLUSION: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.
PMID:
34040193 | DOI:
10.1038/s41436-021-01200-2
June 2, 2021
Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen storage-associated mitochondriopathy
Am J Hum Genet. 2021 May 21:S0002-9297(21)00187-7. doi: 10.1016/j.ajhg.2021.05.003. Online ahead of print.
ABSTRACT
Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.
PMID:
34038740 | DOI:
10.1016/j.ajhg.2021.05.003
May 27, 2021
Implementing Rapid Whole Genome Sequencing in Critical Care: A Qualitative Study of Facilitators and Barriers to New Technology Adoption
Franck LS, Kriz RM, Rego S, Garman K, Hobbs C, Dimmock D.
J Pediatr. 2021 May 20:S0022-3476(21)00496-0. doi: 10.1016/j.jpeds.2021.05.045. Online ahead of print.
ABSTRACT
OBJECTIVE: To characterize the views of members of the multi-disciplinary team regarding the implementation of Rapid Whole Genome Sequencing (rWGS) as a first-tier test for critically ill children in diverse children’s hospital settings.
STUDY DESIGN: Qualitative interviews informed by implementation science theory were conducted with the multi-disciplinary patient care teams and hospital leaders at each of the five tertiary care children’s hospitals involved in a statewide rWGS implementation project.
RESULTS: Our analysis revealed 5 key themes regarding the implementation process across the sites: the need for rWGS champions, educational needs and strategies, negotiating decision-making roles and processes, workflows and workarounds, and perceptions about rWGS. From the findings a composite clinical workflow diagram was developed to summarize all of the processes involved in the implementation of the test, and the key areas where implementation practices differed.
CONCLUSIONS: These findings provide insights for design of interventions to support adoption, scale-up and sustainability of rWGS and other novel technologies in neonatal and pediatric critical care settings.
PMID:
34023348 | DOI:
10.1016/j.jpeds.2021.05.045
May 24, 2021
rWGS
One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation
Lincoln SE, Hambuch T, Zook JM, Bristow SL, Hatchell K, Truty R, Kennemer M, Shirts BH, Fellowes A, Chowdhury S, Klee EW, Mahamdallie S, Cleveland MH, Vallone PM, Ding Y, Seal S, DeSilva W, Tomson FL, Huang C, Garlick RK, Rahman N, Salit M, Kingsmore SF, Ferber MJ, Aradhya S, Nussbaum RL.
Genet Med. 2021 May 18. doi: 10.1038/s41436-021-01187-w. Online ahead of print.
ABSTRACT
PURPOSE: To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions.
METHODS: An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)-based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients.
RESULTS: In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests.
CONCLUSION: The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.
PMID:
3400 7000 | DOI:
10.1038/s41436-021-01187-w
May 19, 2021
Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy
Parenti I, Lehalle D, Nava C, Torti E, Leitão E, Person R, Mizuguchi T, Matsumoto N, Kato M, Nakamura K, de Man SA, Cope H, Shashi V; Undiagnosed Diseases Network, Friedman J, Joset P, Steindl K, Rauch A, Muffels I, van Hasselt PM, Petit F, Smol T, Le Guyader G, Bilan F, Sorlin A, Vitobello A, Philippe C, van de Laar IMBH, van Slegtenhorst MA, Campeau PM, Au PYB, Nakashima M, Saitsu H, Yamamoto T, Nomura Y, Louie RJ, Lyons MJ, Dobson A, Plomp AS, Motazacker MM, Kaiser FJ, Timberlake AT, Fuchs SA, Depienne C, Mignot C.
Hum Genet. 2021 May 4. doi: 10.1007/s00439-021-02283-2. Online ahead of print.
ABSTRACT
Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
PMID:
33944996 | DOI:
10.1007/s00439-021-02283-2
May 11, 2021
