Combination of exome sequencing and immune testing confirms Aicardi-Goutières syndrome type 5 in a challenging pediatric neurology case.

Autor:	Haskell GT; Department of Pathology, Duke University School of Medicine, Durham, North Carolina 27705, USA., Mori M; Brown University, Alpert Medical School, Providence, Rhode Island 02903, USA., Powell C; Department of Pediatrics, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA., Amrhein TJ; Department of Radiology, Duke University School of Medicine, Durham, North Carolina 27705, USA., Rice GI; University of Manchester School of Biological Sciences, Manchester M13 9WL, United Kingdom., Bailey L; Departments of Pediatrics and of Medical Genetics, Duke University, Durham, North Carolina 27705, USA., Strande N; Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.; Department of Pathology and Laboratory Medicine, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA., Weck KE; Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.; Department of Pathology and Laboratory Medicine, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA., Evans JP; Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA., Berg JS; Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA., Kishnani P; Departments of Pediatrics and of Medical Genetics, Duke University, Durham, North Carolina 27705, USA.
Jazyk:	angličtina
Zdroj:	Cold Spring Harbor molecular case studies [Cold Spring Harb Mol Case Stud] 2018 Oct 01; Vol. 4 (5). Date of Electronic Publication: 2018 Oct 01 (Print Publication: 2018).
DOI:	10.1101/mcs.a002758
Abstrakt:	Exome sequencing is increasingly being used to help diagnose pediatric neurology cases when clinical presentations are not specific. However, interpretation of equivocal results that include variants of uncertain significance remains a challenge. In those cases, follow-up testing and clinical correlation can help clarify the clinical relevance of the molecular findings. In this report, we describe the diagnostic odyssey of a 4-year-old girl who presented with global developmental delay and seizures, with leukodystrophy seen on MRI. Clinical evaluation, MRI, and comprehensive metabolic testing were performed, followed by whole-exome sequencing (WES), parental testing, follow-up testing, and retrospective detailed clinical evaluation. WES identified two candidate causative pathogenic variants in SAMHD1 , a gene associated with the recessive condition Aicardi-Goutières syndrome (AGS) type 5 (OMIM 612952): a previously reported pathogenic variant NM_015474 c.602T>A (p.I201N), maternally inherited, and a rare missense variant of uncertain significance, c.1293A>T(p.L431F). Analysis of type I interferon-related biomarkers demonstrated that the patient has an interferon signature characteristic of AGS. Retrospective detailed clinical evaluation showed that the girl has a phenotype consistent with AGS5, a rare neurological condition. These results further define the phenotypic spectrum associated with specific SAMHD1 variants, including heterozygous variants in AGS carriers, and support the idea that autoinflammatory dysregulation is part of the disease pathophysiology. More broadly, this work highlights the issues and methodology involved in ascribing clinical relevance to interpretation of variants detected by WES. (© 2018 Haskell et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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