RESUMEN
Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping â¼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
Asunto(s)
Factor 10 de Crecimiento de Fibroblastos/genética , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/mortalidad , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/mortalidad , Transducción de Señal/genética , Proteínas de Dominio T Box/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Factor 10 de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica , Edad Gestacional , Humanos , Recién Nacido , Enfermedades del Recién Nacido/metabolismo , Enfermedades del Recién Nacido/patología , Pulmón/embriología , Pulmón/crecimiento & desarrollo , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/patología , Masculino , Herencia Materna , Organogénesis , Herencia Paterna , Linaje , Polimorfismo de Nucleótido Simple/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Proteínas de Dominio T Box/metabolismoRESUMEN
Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.