Best practices for the interpretation and reporting of clinical whole genome sequencing
Austin-Tse CA, Jobanputra V, Perry DL, Bick D, Taft RJ, Venner E, Gibbs RA, Young T, Barnett S, Belmont JW, Boczek N, Chowdhury S, Ellsworth KA, Guha S, Kulkarni S, Marcou C, Meng L, Murdock DR, Rehman AU, Spiteri E, Thomas-Wilson A, Kearney HM, Rehm HL; Medical Genome Initiative*.
NPJ Genom Med. 2022 Apr 8;7(1):27. doi: 10.1038/s41525-022-00295-z.
ABSTRACT
Whole genome sequencing (WGS) shows promise as a first-tier diagnostic test for patients with rare genetic disorders. However, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading health care and research organizations in the US and Canada, was formed to expand access to high quality clinical WGS by convening experts and publishing best practices. Here, we present best practice recommendations for the interpretation and reporting of clinical diagnostic WGS, including discussion of challenges and emerging approaches that will be critical to harness the full potential of this comprehensive test.
PMID:
35395838 | DOI:
10.1038/s41525-022-00295-z
April 11, 2022
RPM for NICU and PICU
Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study
Méneret A, Mohammad SS, Cif L, Doummar D, DeGusmao C, Anheim M, Barth M, Damier P, Demonceau N, Friedman J, Gallea C, Gras D, Gurgel-Giannetti J, Innes EA, Necpál J, Riant F, Sagnes S, Sarret C, Seliverstov Y, Paramanandam V, Shetty K, Tranchant C, Doulazmi M, Vidailhet M, Pringsheim T, Roze E.
Mov Disord. 2022 Apr 5. doi: 10.1002/mds.29006. Online ahead of print.
ABSTRACT
BACKGROUND: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine.
OBJECTIVE: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia.
METHODS: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire.
RESULTS: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening.
CONCLUSION: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.
PMID:
35384065 | DOI:
10.1002/mds.29006
April 5, 2022
Genetic Neurologic Disease
El-Hattab-Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: further delineation of the phenotype and genotype
Almannai M, Marafi D, Abdel-Salam GMH, Zaki MS, Duan R, Calame D, Herman I, Levesque FSHA, Elbendary HM, Hegazy I, Chung WK, Kavus H, Saeidi K, Maroofian R, AlHashim A, Al-Otaibi A, Madhi AA, Aboalseood HM, Alasmari A, Houlden H, Gleeson JG, Hunter JV, Posey JE, Lupski JR, El-Hattab AW.
Clin Genet. 2022 Mar 23. doi: 10.1111/cge.14132. Online ahead of print.
ABSTRACT
Homozygous pathogenic variants in WDR45B were first identified in six subjects from three unrelated families with global development delay, refractory seizures, spastic quadriplegia, and brain malformations. Since the initial report in 2018, no further cases have been described. In this report, we present 12 additional individuals from seven unrelated families and their clinical, radiological, and molecular findings. Six different variants in WDR45B were identified, five of which are novel. Microcephaly and global developmental delay were observed in all subjects, and seizures and spastic quadriplegia in most. Common findings on brain imaging include cerebral atrophy, ex-vacuo ventricular dilatation, brainstem volume loss, and symmetric under-opercularization. El-Hattab-Alkuraya syndrome is associated with a consistent phenotype characterized by early onset cerebral atrophy resulting in microcephaly, developmental delay, spastic quadriplegia, and seizures. The phenotype appears to be more severe among individuals with loss-of-function variants whereas those with missense variants were less severely affected suggesting a potential genotype-phenotype correlation in this disorder. A brain imaging pattern emerges which is consistent among individuals with loss-of-function variants and could potentially alert the neuroradiologists or clinician to consider WDR45B-related El-Hattab-Alkuraya syndrome. This article is protected by copyright. All rights reserved.
PMID:
35322404 | DOI:
10.1111/cge.14132
March 23, 2022
Neurogenomics
Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets
Abbas Z, George C, Ancliffe M, Howlett M, Jones AC, Kuchibhotla M, Wechsler-Reya RJ, Gottardo NG, Endersby R.
Front Immunol. 2022 Mar 3;13:837013. doi: 10.3389/fimmu.2022.837013. eCollection 2022.
ABSTRACT
Medulloblastoma is the most common childhood brain cancer. Mainstay treatments of radiation and chemotherapy have not changed in decades and new treatment approaches are crucial for the improvement of clinical outcomes. To date, immunotherapies for medulloblastoma have been unsuccessful, and studies investigating the immune microenvironment of the disease and the impact of current therapies are limited. Preclinical models that recapitulate both the disease and immune environment are essential for understanding immune-tumor interactions and to aid the identification of new and effective immunotherapies. Using an immune-competent mouse model of aggressive Myc-driven medulloblastoma, we characterized the brain immune microenvironment and changes induced in response to craniospinal irradiation, or the medulloblastoma chemotherapies cyclophosphamide or gemcitabine. The role of adaptive immunity in disease progression and treatment response was delineated by comparing survival outcomes in wildtype C57Bl/6J and in mice deficient in Rag1 that lack mature T and B cells. We found medulloblastomas in wildtype and Rag1-deficient mice grew equally fast, and that craniospinal irradiation and chemotherapies extended survival equally in wildtype and Rag1-deficient mice, suggesting that tumor growth and treatment response is independent of T and B cells. Medulloblastomas were myeloid dominant, and in wildtype mice, craniospinal irradiation and cyclophosphamide depleted T and B cells in the brain. Gemcitabine treatment was found to minimally alter the immune populations in the brain, resulting only in a depletion of neutrophils. Intratumorally, we observed an abundance of Iba1+ macrophages, and we show that CD45high cells comprise the majority of immune cells within these medulloblastomas but found that existing markers are insufficient to clearly delineate resident microglia from infiltrating macrophages. Ultimately, brain resident and peripheral macrophages dominate the brain and tumor microenvironment and are not depleted by standard-of-care medulloblastoma therapies. These populations therefore present a favorable target for immunotherapy in combination with front-line treatments.
PMID:
35309309 | PMC:
PMC8928748 | DOI:
10.3389/fimmu.2022.837013
March 3, 2022
Neuro-Oncology
Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome
Angelozzi M, Karvande A, Molin AN, Ritter AL, Leonard JMM, Savatt JM, Douglass K, Myers SM, Grippa M, Tolchin D, Zackai E, Donoghue S, Hurst ACE, Descartes M, Smith K, Velasco D, Schmanski A, Crunk A, Tokita MJ, de Lange IM, van Gassen K, Robinson H, Guegan K, Suri M, Patel C, Bournez M, Faivre L, Tran-Mau-Them F, Baker J, Fabie N, Weaver K, Shillington A, Hopkin RJ, Barge-Schaapveld DQCM, Ruivenkamp CA, Bökenkamp R, Vergano S, Seco Moro MN, Díaz de Bustamante A, Misra VK, Kennelly K, Rogers C, Friedman J, Wigby KM, Lenberg J, Graziano C, Ahrens-Nicklas RC, Lefebvre V.
J Med Genet. 2022 Mar 1:jmedgenet-2021-108375. doi: 10.1136/jmedgenet-2021-108375. Epub ahead of print. PMID: 35232796.
Abstract
Background: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome.
Methods: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients’ phenotypes.
Results: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS.
Conclusion: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.
PMID: 35232796 | DOI: 10.1136/jmedgenet-2021-108375
March 1, 2022
Genetic Neurologic DiseaseNeurogenomics
Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5
Rajan DS, Kour S, Fortuna TR, Cousin MA, Barnett SS, Niu Z, Babovic-Vuksanovic D, Klee EW, Kirmse B, Innes M, Rydning SL, Selmer KK, Vigeland MD, Erichsen AK, Nemeth AH, Millan F, DeVile C, Fawcett K, Legendre A, Sims D, Schnekenberg RP, Burglen L, Mercier S, Bakhtiari S, Martinez-Salas E, Wigby K, Lenberg J, Friedman JR, Kruer MC, Pandey UB.
Front Cell Dev Biol. 2022 Feb 28;10:783762. doi: 10.3389/fcell.2022.783762. eCollection 2022.
ABSTRACT
The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the GEMIN5 gene among seven unrelated families with nine affected individuals presenting with spastic ataxia and cerebellar atrophy. GEMIN5, an RNA-binding protein, has been shown to regulate transcription and translation machinery. GEMIN5 is a component of small nuclear ribonucleoprotein (snRNP) complexes and helps in the assembly of the spliceosome complexes. We found that biallelic GEMIN5 variants cause structural abnormalities in the encoded protein and reduce expression of snRNP complex proteins in patient cells compared with unaffected controls. Finally, knocking out endogenous Gemin5 in mice caused early embryonic lethality, suggesting that Gemin5 expression is crucial for normal development. Our work further expands on the phenotypic spectrum associated with GEMIN5-related disease and implicates the role of GEMIN5 among patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.
PMID:
35295849 | PMC:
PMC8918504 | DOI:
10.3389/fcell.2022.783762
February 28, 2022
Genetic Neurologic Disease
2022: A pivotal year for diagnosis and treatment of rare genetic diseases
Kingsmore SF
Cold Spring Harb Mol Case Stud. 2022 Feb 25:mcs.a006204. doi: 10.1101/mcs.a006204. Online ahead of print.
ABSTRACT
The start of 2022 is an inflection point in the development of diagnostics and treatments for rare genetic diseases in prenatal, pediatric, and adult individuals; the theme of this special issue. Here I briefly review recent developments in the latter two aspects of rare genetic disease diagnostics and treatments.
PMID:
35217563 | DOI:
10.1101/mcs.a006204
February 25, 2022
Rare DiseaseRPM for NICU and PICU
Activated phosphoinositide 3-kinase δ syndrome associated with nephromegaly, growth hormone deficiency, bronchiectasis: a case report
Craig M, Geng B, Wigby K, Phillips SA, Bakhoum C, Naheedy J, Cernelc-Kohan M.
Allergy Asthma Clin Immunol. 2022 Feb 21;18(1):15. doi: 10.1186/s13223-022-00655-5.
ABSTRACT
BACKGROUND: Activated phosphoinositide 3-kinase (PI3K) δ syndrome (APDS) is a rare form of primary immunodeficiency with 243 known cases reported in the literature. Known findings associated with the condition include recurrent sinusitis and bronchitis, bronchiectasis, immune cytopenias, mild developmental delay, splenomegaly, and lymphadenopathy. We report the case of a child with APDS accompanied by unique clinical features: nephromegaly and growth hormone deficiency with associated pituitary anatomic abnormality.
CASE PRESENTATION: The patient is a nine-year-old boy with a heterozygous de novo variant in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ (p.E1021K), previously reported in association with APDS. Our patient, who had no family history of immunodeficiency, exhibits classic findings of this syndrome but also has unique features that extend the phenotypic spectrum of this disorder. At 5 years of age, the patient showed marked growth deceleration and was demonstrated to have growth hormone (GH) deficiency with associated pituitary anatomic abnormality. He started GH therapy with an excellent response. He additionally has bilateral nephromegaly of unclear etiology, microscopic hematuria and proteinuria, asthma, and has developed left hip pain with arthrocentesis consistent with oligoarticular juvenile idiopathic arthritis. At age nine, the patient was referred to genetics and whole exome sequencing revealed APDS. Though there was initial concern that GH may increase risk for malignancy as GH signals through the PI3K pathway, he was allowed to continue treatment as the PI3K pathway was considered constitutively active at baseline.
CONCLUSIONS: Our patient’s unique presentation adds to the clinical information regarding APDS, demonstrates the utility of genetic testing and illustrates the importance of a multidisciplinary collaborative approach in managing this complex syndrome.
PMID:
35189965 | DOI:
10.1186/s13223-022-00655-5
February 21, 2022
Rare Disease
Retrospective identification of prenatal fetal anomalies associated with diagnostic neonatal genomic sequencing results
Zhang-Rutledge K, Owen M, Sweeney NM, Dimmock D, Kingsmore SF, Laurent LC.
Prenat Diagn. 2022 Feb 9. doi: 10.1002/pd.6111. Online ahead of print.
ABSTRACT
OBJECTIVE: To determine which types of fetal anomalies are associated with postnatal diagnoses of genetic diseases by genomic sequencing and to assess how prenatal genomic sequencing could affect clinical management.
METHOD: This was a secondary analysis of the second Newborn Sequencing in Genomic Medicine and Public Health study that compared fetal imaging results in critically ill infants who had actionable versus negative postnatal genomic sequencing results.
RESULTS: Of 213 infants who received genomic sequencing, 80 had available prenatal ultrasounds. Twenty-one (26%) of these were found to have genetic diseases by genomic sequencing. Fourteen (67%) of the 21 with genetic diseases had suspected anomalies prenatally, compared with 33 (56%) of 59 with negative results. Among fetuses with suspected anomalies, genetic diseases were 4.5 times more common in those with multiple anomalies and 6.7 times more common in those with anomalies of the extremities compared to those with negative results. Had the genetic diseases been diagnosed prenatally, clinical management would have been altered in 13 of 14.
CONCLUSION: Critically ill infants with diagnostic genomic sequencing were more likely to have multiple anomalies and anomalies of the extremities on fetal imaging. Among almost all infants with suspected fetal anomalies and diagnostic genomic sequencing results, prenatal diagnosis would have likely altered clinical management.
PMID:
35141907 | DOI:
10.1002/pd.6111
February 9, 2022
RPM for NICU and PICU
Evaluating use of changing technologies for rapid next-generation sequencing in pediatrics
Palmquist R, Jenkins SM, Bentley D, Miller C, Mao R, Meibos B, Bayrak-Toydemir P, Tvrdik T, Nadauld LD, Bleyl SB, Chowdhury S, Ostrander B, Flores-Daboub J, Longo N, Tristani-Firouzi M, Hobbs C, Bonkowsky JL, Brunelli L.
Pediatr Res. 2022 Feb 3. doi: 10.1038/s41390-022-01965-5. Online ahead of print.
ABSTRACT
BACKGROUND: Rapid next-generation sequencing (NGS) offers the potential to shorten the diagnostic process and improve the care of acutely ill children. The goal of this study was to report our findings, including benefits and limitations, of a targeted NGS panel and rapid genome sequencing (rGS) in neonatal and pediatric acute clinical care settings.
METHODS: Retrospective analysis of patient characteristics, diagnostic yields, turnaround time, and changes in management for infants and children receiving either RapSeq, a targeted NGS panel for 4500+ genes, or rGS, at the University of Utah Hospital and Primary Children’s Hospital, from 2015 to 2020.
RESULTS: Over a 5-year period, 142 probands underwent rapid NGS: 66 received RapSeq and 76 rGS. Overall diagnostic yield was 39%. In the majority of diagnostic cases, there were one or more changes in clinical care management. Of note, 7% of diagnoses identified by rGS would not have been identified by RapSeq.
CONCLUSIONS: Our results indicate that rapid NGS impacts acute pediatric care in real-life clinical settings. Although affected by patient selection criteria, diagnostic yields were similar to those from clinical trial settings. Future studies are needed to determine relative advantages, including cost, turnaround time, and benefits for patients, of each approach in specific clinical circumstances.
IMPACT: The use of comprehensive Mendelian gene panels and genome sequencing in the clinical setting allows for early diagnosis of patients in neonatal, pediatric, and cardiac intensive care units and impactful change in management. Diagnoses led to significant changes in management for several patients in lower acuity inpatient units supporting further exploration of the utility of rapid sequencing in these settings. This study reviews the limitations of comparing sequencing platforms in the clinical setting and the variables that should be considered in evaluating diagnostic rates across studies.
PMID:
35115709 | DOI:
10.1038/s41390-022-01965-5
February 3, 2022
RPM for NICU and PICUrWGS
