An intronic variant in TBX4 in a single family with variable and severe pulmonary manifestations

Area of Science:

• Genetics
• Pediatrics
• Pulmonology

Background:

• Neonatal respiratory failure and pulmonary hypertension can present with complex etiologies.
• TBX4 gene mutations are associated with skeletal abnormalities and can impact cardiopulmonary development.
• Understanding genotype-phenotype correlations is crucial for diagnosing rare genetic disorders.

Purpose of the Study:

• To investigate the genetic basis of a biphasic cardiopulmonary presentation in an infant.
• To characterize the functional impact of a novel intronic TBX4 gene variant.
• To illustrate the spectrum of TBX4-associated phenotypes within a family.

Main Methods:

• Clinical case presentation of an infant with respiratory distress and pulmonary hypertension.
• Identification of a TBX4 gene variant using genetic sequencing.
• Analysis of TBX4 gene expression in patient-derived cells.

Main Results:

• An intronic TBX4 variant (c.401+3A>T) was identified in the infant, father, and deceased sister.
• The variant led to reduced TBX4 expression in patient cells.
• Variable expressivity was observed, ranging from acinar dysplasia and neonatal death to skeletal phenotypes and pulmonary hypertension.

Conclusions:

• This intronic TBX4 variant contributes to a spectrum of cardiopulmonary and skeletal phenotypes.
• The study highlights the variable expressivity of TBX4 mutations.
• Genetic diagnostics are essential for identifying and classifying affected individuals in families with TBX4-related disorders.