Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway

Area of Science:

• Developmental Biology
• Human Genetics
• Pathology

Background:

• Primary defects in lung branching morphogenesis cause neonatal lethal pulmonary hypoplasias, with underlying genetic causes incompletely understood.
• Interstitial neonatal lung disorders, including acinar and congenital alveolar dysplasia, represent severe developmental anomalies.

Purpose of the Study:

• To elucidate the pathogenetics of human lung development by investigating genetic factors in lethal pulmonary hypoplasias.
• To identify specific genes and regulatory elements involved in lung organogenesis defects.

Main Methods:

• Studied a collection of deceased individuals with diagnosed interstitial neonatal lung disorders.
• Utilized genetic analysis to identify copy-number variants (CNVs) and single-nucleotide variants (SNVs) in genes like TBX4 and FGF10.
• Analyzed a lung-specific enhancer region at 17q23.1q23.2 in affected individuals and controls.

Main Results:

• Identified rare heterozygous variants in TBX4 or FGF10 in 61% of individuals studied.
• Found overlapping deletions at 17q23.1q23.2, including a lung-specific enhancer, in individuals with lung hypoplasia.
• Observed that individuals with coding variants also had non-coding SNVs in the lung enhancer region, suggesting compound inheritance.

Conclusions:

• TBX4 and FGF10, along with a lung-specific enhancer, are crucial for human lung organogenesis.
• Complex compound inheritance involving coding and non-coding variants contributes to pulmonary hypoplasias.
• Findings help explain the histopathological continuum in rare, lethal lung developmental disorders.