NDLI: Detection of low-prevalence somatic TSC2 mutations in sporadic pulmonary lymphangioleiomyomatosis tissues by deep sequencing

Content Provider	Springer Nature Link
Author	Fujita, Atsushi Ando, Katsutoshi Kobayashi, Etsuko Mitani, Keiko Okudera, Koji Nakashima, Mitsuko Miyatake, Satoko Tsurusaki, Yoshiri Saitsu, Hirotomo Seyama, Kuniaki Miyake, riko Matsumoto, Naomichi
Copyright Year	2015
Abstract	Lymphangioleiomyomatosis (LAM) (MIM #606690) is a rare lung disorder leading to respiratory failure associated with progressive cystic destruction due to the proliferation and infiltration of abnormal smooth muscle-like cells (LAM cells). LAM can occur alone (sporadic LAM, S-LAM) or combined with tuberous sclerosis complex (TSC-LAM). TSC is caused by a germline heterozygous mutation in either TSC1 or TSC2, and TSC-LAM is thought to occur as a result of a somatic mutation (second hit) in addition to a germline mutation in TSC1 or TSC2 (first hit). S-LAM is also thought to occur under the two-hit model involving a somatic mutation and/or loss of heterozygosity in TSC2. To identify TSC1 or TSC2 changes in S-LAM patients, the two genes were analyzed by deep next-generation sequencing (NGS) using genomic DNA from blood leukocytes (n = 9), LAM tissue from lung (n = 7), LAM cultured cells (n = 4), or LAM cell clusters (n = 1). We identified nine somatic mutations in six of nine S-LAM patients (67 %) with mutant allele frequencies of 1.7–46.2 %. Three of these six patients (50 %) showed two different TSC2 mutations with allele frequencies of 1.7–28.7 %. Furthermore, at least five mutations with low prevalence (<20 % of allele frequency) were confirmed by droplet digital PCR. As LAM tissues are likely to be composed of heterogeneous cell populations, mutant allele frequencies can be low. Our results confirm the consistent finding of TSC2 mutations in LAM samples, and highlight the benefit of laser capture microdissection and in-depth allele analyses for detection, such as NGS.
Starting Page	61
Ending Page	68
Page Count	8
File Format	PDF
ISSN	03406717
Journal	Human Genetics
Volume Number	135
Issue Number	1
e-ISSN	14321203
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2015-11-12
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Human Genetics Molecular Medicine Gene Function Metabolic Diseases
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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