Identification of Heterozygous Single- and Multi-exon Deletions in IL7R by Whole Exome Sequencing.

Engelhardt, Karin R; Xu, Yaobo; Grainger, Angela; Germani Batacchi, Mila G C; Swan, David J; Willet, Joseph D P; Abd Hamid, Intan J; Agyeman, Philipp; Barge, Dawn; Bibi, Shahnaz; Jenkins, Lucy; Flood, Terence J; Abinun, Mario; Slatter, Mary A; Gennery, Andrew R; Cant, Andrew J; Santibanez Koref, Mauro; Gilmour, Kimberly; Hambleton, Sophie (2017). Identification of Heterozygous Single- and Multi-exon Deletions in IL7R by Whole Exome Sequencing. Journal of clinical immunology, 37(1), pp. 42-50. Springer 10.1007/s10875-016-0343-9

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PURPOSE We aimed to achieve a retrospective molecular diagnosis by applying state-of-the-art genomic sequencing methods to past patients with T-B+NK+ severe combined immunodeficiency (SCID). We included identification of copy number variations (CNVs) by whole exome sequencing (WES) using the CNV calling method ExomeDepth to detect gene alterations for which routine Sanger sequencing analysis is not suitable, such as large heterozygous deletions. METHODS Of a total of 12 undiagnosed patients with T-B+NK+ SCID, we analyzed eight probands by WES, using GATK to detect single nucleotide variants (SNVs) and small insertions and deletions (INDELs) and ExomeDepth to detect CNVs. RESULTS We found heterozygous single- or multi-exon deletions in IL7R, a known disease gene for autosomal recessive T-B+NK+ SCID, in four families (seven patients). In three families (five patients), these deletions coexisted with a heterozygous splice site or nonsense mutation elsewhere in the same gene, consistent with compound heterozygosity. In our cohort, about a quarter of T-B+NK+ SCID patients (26%) had such compound heterozygous IL7R deletions. CONCLUSIONS We show that heterozygous IL7R exon deletions are common in T-B+NK+ SCID and are detectable by WES. They should be considered if Sanger sequencing fails to detect homozygous or compound heterozygous IL7R SNVs or INDELs.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Paediatric Infectiology

UniBE Contributor:

Agyeman, Philipp

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0271-9142

Publisher:

Springer

Language:

English

Submitter:

Philipp Agyeman

Date Deposited:

28 Jul 2017 08:08

Last Modified:

28 Jul 2017 08:08

Publisher DOI:

10.1007/s10875-016-0343-9

PubMed ID:

27807805

Uncontrolled Keywords:

IL7R; SCID; compound heterozygous; copy number variation; whole exome sequencing

BORIS DOI:

10.7892/boris.96016

URI:

https://boris.unibe.ch/id/eprint/96016

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