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



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.



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.



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.
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. karin.engelhardt@newcastle.ac.uk.
Karin R
KR
Engelhardt
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Yaobo
Y
Xu
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Angela
A
Grainger
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Mila G C
MG
Germani Batacchi
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
David J
DJ
Swan
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Joseph D P
JD
Willet
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Intan J
IJ
Abd Hamid
Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Philipp
P
Agyeman
Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Dawn
D
Barge
NE Thames Regional Genetics Service, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Shahnaz
S
Bibi
NE Thames Regional Genetics Service, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Lucy
L
Jenkins
Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Terence J
TJ
Flood
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Mario
M
Abinun
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Mary A
MA
Slatter
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Andrew R
AR
Gennery
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Andrew J
AJ
Cant
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Mauro
M
Santibanez Koref
Immunology, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Kimberly
K
Gilmour
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Sophie
S
Hambleton
D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005091:Exons; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D054643:INDEL Mutation; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D050799:STAT5 Transcription Factor / Q000378:metabolism; D017384:Sequence Deletion; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000628:therapy; D000073359:Exome Sequencing; D057188:Workflow
D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor
IL7R; SCID; compound heterozygous; copy number variation; whole exome sequencing