Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity
CLINICAL GENETICS
Authors: Karolak, Justyna A.; Szafranski, Przemyslaw; Kilner, David; Patel, Chirag; Scurry, Bonnie; Kinning, Esther; Chandler, Kate; Jhangiani, Shalini N.; Akdemir, Zeynep H. Coban; Lupski, James R.; Popek, Edwina; Stankiewicz, Pawel
Abstract
The canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full-term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes.
Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets
NATURE COMMUNICATIONS
Authors: Newel, Felicity; Kong, Yan; Wilmott, James S.; Johansson, Peter A.; Ferguson, Peter M.; Cui, Chuanliang; Li, Zhongwu; Kazakoff, Stephen H.; Burke, Hazel; Dodds, Tristan J.; Patch, Ann-Marie; Nones, Katia; Tembe, Varsha; ShanG, Ping; van der Weyden, Louise; WongH, Kim; Holmes, Oliver; Lo, Serigne; Leonardl, Conrad; Wood, Scott; Xu, Qinying; Rawson, Robert, V; Mukhopadhyay, Pamela; Dummer, Reinhard; Levesque, Mitchell P.; Jonsson, Goran; Wang, Xuan; Yeh, Iwei; Wu, Hong; Joseph, Nancy; Bastian, Boris C.; Long, Georgina, V; Spillane, Andrew J.; Shannon, Kerwin F.; Thompson, John F.; Saw, Robyn P. M.; Adams, David J.; Si, Lu; Pearson, John, V; Hayward, Nicholas K.; Waddell, Nicola; Mann, Graham J.; Guo, Jun; Scolyer, Richard A.
Abstract
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
COA
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