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2016 ; 7
(ä): 466
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Diagnostics of Primary Immunodeficiencies through Next-Generation Sequencing
#MMPMID27872624
Gallo V
; Dotta L
; Giardino G
; Cirillo E
; Lougaris V
; D'Assante R
; Prandini A
; Consolini R
; Farrow EG
; Thiffault I
; Saunders CJ
; Leonardi A
; Plebani A
; Badolato R
; Pignata C
Front Immunol
2016[]; 7
(ä): 466
PMID27872624
show ga
BACKGROUND: Recently, a growing number of novel genetic defects underlying
primary immunodeficiencies (PIDs) have been identified, increasing the number of
PID up to more than 250 well-defined forms. Next-generation sequencing (NGS)
technologies and proper filtering strategies greatly contributed to this rapid
evolution, providing the possibility to rapidly and simultaneously analyze large
numbers of genes or the whole exome. OBJECTIVE: To evaluate the role of targeted
NGS and whole exome sequencing (WES) in the diagnosis of a case series,
characterized by complex or atypical clinical features suggesting a PID,
difficult to diagnose using the current diagnostic procedures. METHODS: We
retrospectively analyzed genetic variants identified through targeted NGS or WES
in 45 patients with complex PID of unknown etiology. RESULTS: Forty-seven
variants were identified using targeted NGS, while 5 were identified using WES.
Newly identified genetic variants were classified into four groups: (I)
variations associated with a well-defined PID, (II) variations associated with
atypical features of a well-defined PID, (III) functionally relevant variations
potentially involved in the immunological features, and (IV) non-diagnostic
genotype, in whom the link with phenotype is missing. We reached a conclusive
genetic diagnosis in 7/45 patients (~16%). Among them, four patients presented
with a typical well-defined PID. In the remaining three cases, mutations were
associated with unexpected clinical features, expanding the phenotypic spectrum
of typical PIDs. In addition, we identified 31 variants in 10 patients with
complex phenotype, individually not causative per se of the disorder. CONCLUSION:
NGS technologies represent a cost-effective and rapid first-line genetic approach
for the evaluation of complex PIDs. WES, despite a moderate higher cost compared
to targeted, is emerging as a valuable tool to reach in a timely manner, a PID
diagnosis with a considerable potential to draw genotype-phenotype correlation.
Nevertheless, a large fraction of patients still remains without a conclusive
diagnosis. In these patients, the sum of non-diagnostic variants might be proven
informative in future studies with larger cohorts of patients.
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