Insights into the perinatal phenotype of Kabuki syndrome in infants identified by genome-wide sequencing
Wigby K, Hammer M, Tokita M, Patel P, Jones MC, Larson A, Bartolomei FV, Dykzeul N, Slavotinek A, Yip T, Bandres-Ciga S, Simpson BN, Suhrie K, Shankar S, Veith R, Bragg J, Powell C, Kingsmore SF, Dimmock D, Maron J, Davis J, Del Campo M.
Am J Med Genet A. 2023 Jan 18. doi: 10.1002/ajmg.a.63097. Online ahead of print.
Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder.
January 18, 2023
Rare DiseaseRPM for NICU and PICU
Reversibility and developmental neuropathology of linear nevus sebaceous syndrome caused by dysregulation of the RAS pathway
Kim YE, Kim YS, Lee HE, So KH, Choe Y, Suh BC, Kim JH, Park SK, Mathern GW, Gleeson JG, Rah JC, Baek ST.
Cell Rep. 2023 Jan 14;42(1):112003. doi: 10.1016/j.celrep.2023.112003. Online ahead of print.
Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRASG12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRASG12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRASG12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRASG12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRASG12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway.
January 14, 2023
Novel Approach to Improve the Identification of the Bleeding Phenotype in Noonan Syndrome and Related RASopathies
Bruno L, Lenberg J, Le D, Dimmock D, Thornburg CD, Briggs B.
J Pediatr. 2023 Jan 13:S0022-3476(23)00019-7. doi: 10.1016/j.jpeds.2022.12.036. Online ahead of print.
OBJECTIVES: To characterize bleeding phenotype in Noonan Syndrome, to test the utility of following national guidelines in detecting this phenotype, to evaluate thromboelastography (TEG) as a diagnostic tool and to evaluate the cohort for genotype-phenotype correlations.
STUDY DESIGN: Participants with a clinical diagnosis NS or related RASopathy were enrolled in a cohort study. Study procedures included clinical bleeding assessment, coagulation testing per guidelines and hematology consultation. TEG was completed in a subset and genetic testing was conducted for those without a molecular diagnosis. International Society of Haemostasis and Thrombosis Bleeding Assessment Tool (ISTH-BAT) scores were calculated with hematology consultation. Bleeding phenotype was defined as abnormal bleeding score.
RESULTS: Twenty participants enrolled; 12completed clinical and laboratory evaluation, five of whom met the definition for bleeding phenotype. Four of the five participants with a bleeding phenotype had platelet aggregation defects and at least one additional coagulation defect. TEG was performed in nine participants, four with bleeding phenotype and five without, and results were normal in all cases. No genotype-phenotype correlation was found.
CONCLUSION: Five of 20 participants had a bleeding phenotype identified. Based on available data we do not recommend incorporating TEG into clinical practice for NS patients. Platelet aggregation defects were the most common abnormalities, which would not be detected on Tier 1 testing of current guidelines, therefore we propose a new algorithm.
January 13, 2023
Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development
Chung C, Yang X, Bae T, Vong KI, Mittal S, Donkels C, Westley Phillips H, Li Z, Marsh APL, Breuss MW, Ball LL, Garcia CAB, George RD, Gu J, Xu M, Barrows C, James KN, Stanley V, Nidhiry AS, Khoury S, Howe G, Riley E, Xu X, Copeland B, Wang Y, Kim SH, Kang HC, Schulze-Bonhage A, Haas CA, Urbach H, Prinz M, Limbrick DD Jr, Gurnett CA, Smyth MD, Sattar S, Nespeca M, Gonda DD, Imai K, Takahashi Y, Chen HH, Tsai JW, Conti V, Guerrini R, Devinsky O, Silva WA Jr, Machado HR, Mathern GW, Abyzov A, Baldassari S, Baulac S; Focal Cortical Dysplasia Neurogenetics Consortium; Brain Somatic Mosaicism Network; Gleeson JG.
Nat Genet. 2023 Jan 12. doi: 10.1038/s41588-022-01276-9. Online ahead of print.
Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.
January 12, 2023
Gene-Folic Acid Interactions and Risk of Conotruncal Heart Defects: Results from the National Birth Defects Prevention Study
Webber DM, Li M, MacLeod SL, Tang X, Levy JW, Karim MA, Erickson SW, Hobbs CA, The National Birth Defects Prevention Study.
Genes (Basel). 2023 Jan 9;14(1):180. doi: 10.3390/genes14010180.
Conotruncal heart defects (CTDs) are heart malformations that affect the cardiac outflow tract and typically cause significant morbidity and mortality. Evidence from epidemiological studies suggests that maternal folate intake is associated with a reduced risk of heart defects, including CTD. However, it is unclear if folate-related gene variants and maternal folate intake have an interactive effect on the risk of CTDs. In this study, we performed targeted sequencing of folate-related genes on DNA from 436 case families with CTDs who are enrolled in the National Birth Defects Prevention Study and then tested for common and rare variants associated with CTD. We identified risk alleles in maternal MTHFS (ORmeta = 1.34; 95% CI 1.07 to 1.67), maternal NOS2 (ORmeta = 1.34; 95% CI 1.05 to 1.72), fetal MTHFS (ORmeta = 1.35; 95% CI 1.09 to 1.66), and fetal TCN2 (ORmeta = 1.38; 95% CI 1.12 to 1.70) that are associated with an increased risk of CTD among cases without folic acid supplementation. We detected putative de novo mutations in genes from the folate, homocysteine, and transsulfuration pathways and identified a significant association between rare variants in MGST1 and CTD risk. Results suggest that periconceptional folic acid supplementation is associated with decreased risk of CTD among individuals with susceptible genotypes.
January 9, 2023
Breaking Barriers to Rapid Whole Genome Sequencing in Pediatrics: Michigan’s Project Baby Deer
Bupp CP, Ames EG, Arenchild MK, Caylor S, Dimmock DP, Fakhoury JD, Karna P, Lehman A, Meghea CI, Misra V, Nolan DA, O’Shea J, Sharangpani A, Franck LS, Scheurer-Monaghan A.
Children. 2023; 10(1):106. https://doi.org/10.3390/children10010106
The integration of precision medicine in the care of hospitalized children is ever evolving. However, access to new genomic diagnostics such as rapid whole genome sequencing (rWGS) is hindered by barriers in implementation. Michigan’s Project Baby Deer (PBD) is a multi-center collaborative effort that sought to break down barriers to access by offering rWGS to critically ill neonatal and pediatric inpatients in Michigan. The clinical champion team used a standardized approach with inclusion and exclusion criteria, shared learning, and quality improvement evaluation of the project’s impact on the clinical outcomes and economics of inpatient rWGS. Hospitals, including those without on-site geneticists or genetic counselors, noted positive clinical impacts, accelerating time to definitive treatment for project patients. Between 95–214 hospital days were avoided, net savings of $4155 per patient, and family experience of care was improved. The project spurred policy advancement when Michigan became the first state in the United States to have a Medicaid policy with carve-out payment to hospitals for rWGS testing. This state project demonstrates how front-line clinician champions can directly improve access to new technology for pediatric patients and serves as a roadmap for expanding clinical implementation of evidence-based precision medicine technologies.
January 4, 2023
RPM for NICU and PICUrWGS
Control-independent mosaic single nucleotide variant detection with DeepMosaic
Yang X, Xu X, Breuss MW, Antaki D, Ball LL, Chung C, Shen J, Li C, George RD, Wang Y, Bae T, Cheng Y, Abyzov A, Wei L, Alexandrov LB, Sebat JL; NIMH Brain Somatic Mosaicism Network; Gleeson JG.
Nat Biotechnol. 2023 Jan 2. doi: 10.1038/s41587-022-01559-w. Online ahead of print.
Mosaic variants (MVs) reflect mutagenic processes during embryonic development and environmental exposure, accumulate with aging and underlie diseases such as cancer and autism. The detection of noncancer MVs has been computationally challenging due to the sparse representation of nonclonally expanded MVs. Here we present DeepMosaic, combining an image-based visualization module for single nucleotide MVs and a convolutional neural network-based classification module for control-independent MV detection. DeepMosaic was trained on 180,000 simulated or experimentally assessed MVs, and was benchmarked on 619,740 simulated MVs and 530 independent biologically tested MVs from 16 genomes and 181 exomes. DeepMosaic achieved higher accuracy compared with existing methods on biological data, with a sensitivity of 0.78, specificity of 0.83 and positive predictive value of 0.96 on noncancer whole-genome sequencing data, as well as doubling the validation rate over previous best-practice methods on noncancer whole-exome sequencing data (0.43 versus 0.18). DeepMosaic represents an accurate MV classifier for noncancer samples that can be implemented as an alternative or complement to existing methods.
January 2, 2023
Rapid genome sequencing identifies novel variants in complement factor I
Rodriguez KM, Vaught J, Dilley M, Ellsworth K, Heinen A, Abud EM, Zhang Y, Smith RJH, Sheets R, Geng B, Hoffman HM, Worthen HM, Dimmock D, Coufal NG.
Cold Spring Harb Mol Case Stud. 2022 Dec 28;8(7):a006239. doi: 10.1101/mcs.a006239. Print 2022 Dec.
Complement factor I deficiency (CFID; OMIM #610984) is a rare immunodeficiency caused by deficiencies in the serine protease complement factor I (CFI). CFID is characterized by predisposition to severe pneumococcal infection, often in infancy. We report a previously healthy adolescent male who presented with respiratory failure secondary to pneumococcal pneumonia and severe systemic inflammatory response. Rapid genome sequencing (rGS) identified compound heterozygous variants in CFI in the proband, with a novel maternally inherited likely pathogenic variant, a single nucleotide deletion resulting in premature stop (c.1646del; p.Asn549ThrfsTer25) and a paternally inherited novel likely pathogenic deletion (Chr 4:110685580-110692197del).
December 28, 2022
NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry
Stanclift CR, Dwight SS, Lee K, Eijkenboom QL, Wilsey M, Wilsey K, Kobayashi ES, Tong S, Bainbridge MN.
December 17, 2022