An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm
Am J Hum Genet. 2020 Nov 5;107(5):942-952. doi: 10.1016/j.ajhg.2020.10.003. ABSTRACT The second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study was a randomized, controlled trial of rapid whole-genome sequencing (rWGS) or rapid whole-exome sequencing (rWES) in infants with diseases of unknown etiology in intensive care units (ICUs). Gravely ill infants were not randomized […]
Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing
NPJ Genom Med. 2020 Nov 2;5:49. doi: 10.1038/s41525-020-00155-8. eCollection 2020. ABSTRACT Understanding causes of infant mortality shapes public health policy and prioritizes diseases for investments in surveillance, intervention and medical research. Rapid genomic sequencing has created a novel opportunity to decrease infant mortality associated with treatable genetic diseases. Herein, we sought to measure the contribution […]
KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation
Brain. 2020 Dec 5;143(11):3242-3261. doi: 10.1093/brain/awaa304. ABSTRACT Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as […]
Novel Protein Biomarkers of Monoamine Metabolism Defects Correlate with Disease Severity
Mov Disord. 2021 Mar;36(3):690-703. doi: 10.1002/mds.28362. Epub 2020 Nov 5. ABSTRACT BACKGROUND: Genetic defects of monoamine neurotransmitters are rare neurological diseases amenable to treatment with variable response. They are major causes of early parkinsonism and other spectrum of movement disorders including dopa-responsive dystonia. OBJECTIVES: The objective of this study was to conduct proteomic studies in […]
A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder
Neurol Sci. 2020 Oct 29. doi: 10.1007/s10072-020-04843-2. Online ahead of print. ABSTRACT At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, […]
Rapid whole-genome sequencing identifies a homozygous novel variant, His540Arg, in HSD17B4 resulting in D-bifunctional protein deficiency disorder diagnosis
Cold Spring Harb Mol Case Stud. 2020 Dec 17;6(6):a005496. doi: 10.1101/mcs.a005496. Print 2020 Dec. ABSTRACT Rapid whole-genome sequencing (rWGS) allows for a diagnosis to be made quickly and impact medical management, particularly in critically ill children. Variants identified by this approach are often not identified using other testing methodologies, such as carrier screening or gene […]
ECHS1 disease in two unrelated families of Samoan descent: Common variant – rare disorder
Am J Med Genet A. 2021 Jan;185(1):157-167. doi: 10.1002/ajmg.a.61936. Epub 2020 Oct 28. ABSTRACT Mutations in the short-chain enoyl-CoA hydratase (SCEH) gene, ECHS1, cause a rare autosomal recessive disorder of valine catabolism. Patients usually present with developmental delay, regression, dystonia, feeding difficulties, and abnormal MRI with bilateral basal ganglia involvement. We present clinical, biochemical, molecular, […]
Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease
NPJ Genom Med. 2020 Oct 23;5:47. doi: 10.1038/s41525-020-00154-9. eCollection 2020. ABSTRACT Whole-genome sequencing (WGS) has shown promise in becoming 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 […]
Insight into developmental mechanisms of global and focal migration disorders of cortical development
Curr Opin Neurobiol. 2020 Oct 21;66:77-84. doi: 10.1016/j.conb.2020.10.005. Online ahead of print. ABSTRACT Cortical development involves neurogenesis followed by migration, maturation, and myelination of immature neurons. Disruptions in these processes can cause malformations of cortical development (MCD). Radial glia (RG) are the stem cells of the brain, both generating neurons and providing the scaffold upon […]
Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome
Am J Med Genet A. 2021 Jan;185(1):119-133. doi: 10.1002/ajmg.a.61926. Epub 2020 Oct 24. ABSTRACT Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a “Dubowitz-like” condition, although no single gene has been implicated as […]