TY - JOUR
T1 - Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism
T2 - A Five-Year Cumulative Cohort
AU - McNulty, Samantha N.
AU - Evenson, Michael J.
AU - Corliss, Meagan M.
AU - Love-Gregory, Latisha D.
AU - Schroeder, Molly C.
AU - Cao, Yang
AU - Lee, Yi Shan
AU - Drolet, Beth A.
AU - Neidich, Julie A.
AU - Cottrell, Catherine E.
AU - Heusel, Jonathan W.
N1 - Publisher Copyright:
© 2019
PY - 2019/10/3
Y1 - 2019/10/3
N2 - Disorders of somatic mosaicism (DoSM) are a diverse group of syndromic and non-syndromic conditions caused by mosaic variants in genes that regulate cell survival and proliferation. Despite overlap in gene space and technical requirements, few clinical labs specialize in DoSM compared to oncology. We adapted a high-sensitivity next-generation sequencing cancer assay for DoSM in 2014. Some 343 individuals have been tested over the past 5 years, 58% of which had pathogenic and likely pathogenic (P/LP) findings, for a total of 206 P/LP variants in 22 genes. Parameters associated with the high diagnostic yield were: (1) deep sequencing (∼2,000× coverage), (2) a broad gene set, and (3) testing affected tissues. Fresh and formalin-fixed paraffin embedded tissues performed equivalently for identification of P/LP variants (62% and 71% of individuals, respectively). Comparing cultured fibroblasts to skin biopsies suggested that culturing might boost the allelic fraction of variants that confer a growth advantage, specifically gain-of-function variants in PIK3CA. Buccal swabs showed high diagnostic sensitivity in case subjects where disease phenotypes manifested in the head or brain. Peripheral blood was useful as an unaffected comparator tissue to determine somatic versus constitutional origin but had poor diagnostic sensitivity. Descriptions of all tested individuals, specimens, and P/LP variants included in this cohort are available to further the study of the DoSM population.
AB - Disorders of somatic mosaicism (DoSM) are a diverse group of syndromic and non-syndromic conditions caused by mosaic variants in genes that regulate cell survival and proliferation. Despite overlap in gene space and technical requirements, few clinical labs specialize in DoSM compared to oncology. We adapted a high-sensitivity next-generation sequencing cancer assay for DoSM in 2014. Some 343 individuals have been tested over the past 5 years, 58% of which had pathogenic and likely pathogenic (P/LP) findings, for a total of 206 P/LP variants in 22 genes. Parameters associated with the high diagnostic yield were: (1) deep sequencing (∼2,000× coverage), (2) a broad gene set, and (3) testing affected tissues. Fresh and formalin-fixed paraffin embedded tissues performed equivalently for identification of P/LP variants (62% and 71% of individuals, respectively). Comparing cultured fibroblasts to skin biopsies suggested that culturing might boost the allelic fraction of variants that confer a growth advantage, specifically gain-of-function variants in PIK3CA. Buccal swabs showed high diagnostic sensitivity in case subjects where disease phenotypes manifested in the head or brain. Peripheral blood was useful as an unaffected comparator tissue to determine somatic versus constitutional origin but had poor diagnostic sensitivity. Descriptions of all tested individuals, specimens, and P/LP variants included in this cohort are available to further the study of the DoSM population.
KW - brain malformation
KW - macrocephaly
KW - megalencephaly
KW - mosaicism
KW - nevus syndrome
KW - overgrowth syndrome
KW - somatic overgrowth
KW - vascular malformation
UR - http://www.scopus.com/inward/record.url?scp=85072278237&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2019.09.002
DO - 10.1016/j.ajhg.2019.09.002
M3 - Article
C2 - 31585106
AN - SCOPUS:85072278237
SN - 0002-9297
VL - 105
SP - 734
EP - 746
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -