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Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies.

ABSTRACT: BACKGROUND:Systemic lupus erythematosus (SLE) comprise a diverse range of clinical manifestations. To date, more than 30 single gene causes of lupus/lupus like syndromes in humans have been identified. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to phenotypic and genetic heterogeneity. METHODS:We employed whole exome sequencing (WES) in patients presenting with childhood-onset lupus with severe and/or atypical presentations to identify cases that are explained by a single-gene (monogenic) cause. RESULTS:From January 2015 to June 2018 15 new cases of childhood-onset SLE were diagnosed in Edmond and Lily Safra Children's Hospital. By WES we identified causative mutations in four subjects in five different genes: C1QC, SLC7A7, MAN2B1, PTEN and STAT1. No molecular diagnoses were established on clinical grounds prior to genetic testing. CONCLUSIONS:We identified a significant fraction of monogenic SLE etiologies using WES and confirm the genetic locus heterogeneity in childhood-onset lupus. These results highlight the importance of establishing a genetic diagnosis for children with severe or atypical lupus by providing accurate and early etiology-based diagnoses and improving subsequent clinical management.

SUBMITTER: Tirosh I

PROVIDER: S-EPMC6668194 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies.

Tirosh Irit I Spielman Shiri S Barel Ortal O Ram Reut R Stauber Tali T Paret Gideon G Rubinsthein Marina M Pessach Itai M IM Gerstein Maya M Anikster Yair Y Shukrun Rachel R Dagan Adi A Adler Katerina K Pode-Shakked Ben B Volkov Alexander A Perelman Marina M Greenberger Shoshana S Somech Raz R Lahav Einat E Majmundar Amar J AJ Padeh Shai S Hildebrandt Friedhelm F Vivante Asaf A

Pediatric rheumatology online journal 20190730 1

<h4>Background</h4>Systemic lupus erythematosus (SLE) comprise a diverse range of clinical manifestations. To date, more than 30 single gene causes of lupus/lupus like syndromes in humans have been identified. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to phenotypic and genetic heterogeneity.<h4>Methods</h4>We employed whole exome sequencing (WES) in patients presenting with childhood-onset lupus with severe and/or atypical presentations to identif ...[more]

PMID: 31362757

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Project description:Childhood apraxia of speech (CAS) is a rare, severe, persistent pediatric motor speech disorder with associated deficits in sensorimotor, cognitive, language, learning and affective processes. Among other neurogenetic origins, CAS is the disorder segregating with a mutation in FOXP2 in a widely studied, multigenerational London family. We report the first whole-exome sequencing (WES) findings from a cohort of 10 unrelated participants, ages 3 to 19 years, with well-characterized CAS.As part of a larger study of children and youth with motor speech sound disorders, 32 participants were classified as positive for CAS on the basis of a behavioral classification marker using auditory-perceptual and acoustic methods that quantify the competence, precision and stability of a speaker's speech, prosody and voice. WES of 10 randomly selected participants was completed using the Illumina Genome Analyzer IIx Sequencing System. Image analysis, base calling, demultiplexing, read mapping, and variant calling were performed using Illumina software. Software developed in-house was used for variant annotation, prioritization and interpretation to identify those variants likely to be deleterious to neurodevelopmental substrates of speech-language development.Among potentially deleterious variants, clinically reportable findings of interest occurred on a total of five chromosomes (Chr3, Chr6, Chr7, Chr9 and Chr17), which included six genes either strongly associated with CAS (FOXP1 and CNTNAP2) or associated with disorders with phenotypes overlapping CAS (ATP13A4, CNTNAP1, KIAA0319 and SETX). A total of 8 (80%) of the 10 participants had clinically reportable variants in one or two of the six genes, with variants in ATP13A4, KIAA0319 and CNTNAP2 being the most prevalent.Similar to the results reported in emerging WES studies of other complex neurodevelopmental disorders, our findings from this first WES study of CAS are interpreted as support for heterogeneous genetic origins of this pediatric motor speech disorder with multiple genes, pathways and complex interactions. We also submit that our findings illustrate the potential use of WES for both gene identification and case-by-case clinical diagnostics in pediatric motor speech disorders.

Dataset Information

Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies.

Publications

Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies.

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