Table 3.
Clinical Features of Individuals Heterozygous for TBX4 Gain-of-Function Missense Variants
| Variant | Demographics | Primary Lung Phenotype; Age at Diagnosis | Details of Lung Disease and Comorbidities | Skeletal Features | Follow-Up | Pedigree Information | ACMG Classification; Population Frequency (gnomAD Exomes) |
|---|---|---|---|---|---|---|---|
| c.104C>T; p.Ala35Val | Dutch PAH patient cohort (40) | PAH; adult onset | N/A | N/A | Deceased (unavailable details) | N/A | Likely benign; 0.009 |
| c.432G>T; p.Met144Ile | Female, White Hispanic (22) | IPAH; 28 yr | Clinical diagnosis of possible PVOD due to radiological findings and reduced diffusion capacity. Histopathological findings (explanted lung tissue): typical PAH features, no evidence of PVOD or ILD. Unknown smoking status. | Absent | Clinical deterioration with bilateral lung transplantation 9 yr after diagnosis | Maternally inherited variant, PAH ruled out at 67 yr | Pathogenic; 3.98 × 10−6 |
| c.432G>T; p.Met144Ile | Male, White Hispanic (22) | PVOD; 62 yr | Radiological findings typical of PVOD. Signs of heart failure, severe respiratory insufficiency. Not eligible for lung transplant because of advanced age and comorbidities. Unknown smoking status. | Absent | Deceased (26 mo after diagnosis) | No known family history of PAH/SPS. Deceased parents before PAH diagnosis. Genetic counseling provided to the rest of the family (declined genetic testing) | Pathogenic; 3.98 × 10−6 |
| c.652G>A; p.Val218Met | Female, White European (24) | chILD; 5 mo | Lung biopsy at 7 yr: diffuse alveolar simplification, moderate thickened PA muscular wall, and PA fibrointimal proliferation. PFO, microcephaly, hearing loss. | Short stature, no SPS features | 10 yr: chILD, moderate pulmonary hypertension | Parents not tested | VUS; 1.23 × 10−4 |
| c.743G>T; p.Gly248Val | Dutch family (16, 40) | — | Family members screened for PAH by echocardiography with none fulfilling diagnostic criteria (unavailable details). | Classical SPS phenotype, including patellar and pelvic anomalies | N/A | Three-generation pedigree (family A) (16) | Pathogenic; not reported |
| c.809T>G; p.Ile270Ser | Female, White European (37) | IPAH; 57 yr | Functional class III at diagnosis. Asthma, HTN, obesity, sleep apnea. Never smoked. | N/A | Alive (1-yr follow-up) | N/A | Likely pathogenic; 4.00 × 10−6 |
| c.1070C>T; p.Ala357Val | Female, White British (3) | IPAH; 81 yr | Functional class III at diagnosis. Radiological findings included minor bronchial wall thickening, no evidence of PVOD except mediastinal nodes, no interstitial lung disease. Hypothyroidism, IHD, T2DM, HTN, breast cancer. Never smoked. | N/A | Died in hospice 7 mo after diagnosis (progressive heart failure) | N/A | VUS; 1.99 × 10−5 |
| c.1102C>T; p.Arg368Cys | Female, African Caribbean (3) | IPAH; 39 yr | Functional class III at diagnosis. Radiological findings are typical of PAH, no lung disease, PFO, hypothyroidism, chronic subdural hematoma. Unknown smoking status. | N/A | Deceased (50 yr) | N/A | VUS; 5.58 × 10−5 |
| c.1592A>G; p.Gln531Arg | Dutch family (16, 40) | — | Family members screened for PAH by echocardiography with none fulfilling diagnostic criteria (unavailable details) | Classical SPS phenotype, including patellar and pelvic anomalies | N/A | Three-generation pedigree (family C) (16) | Likely pathogenic; not reported |
Definition of abbreviations: ACMG = American College of Medical Genetics and Genomics; chILD = childhood-onset interstitial lung disease; HTN = systemic hypertension; IHD = ischemic heart disease; ILD = interstitial lung disease; IPAH = idiopathic pulmonary arterial hypertension; N/A = not available; PA = pulmonary artery; PAH = pulmonary arterial hypertension; PFO = patent foramen ovale; PVOD = pulmonary venoocclusive disease; SPS = small patella syndrome; T2DM = type 2 diabetes mellitus; TBX4 = T-BOX transcription factor 4; VUS = variant of uncertain clinical significance.