Alternative titles; symbols
ORPHA: 422; DO: 14557;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q29 | Pulmonary hypertension, primary, 5 | 265400 | Autosomal recessive | 3 | ATP13A3 | 610232 |
A number sign (#) is used with this entry because of evidence that primary pulmonary hypertension-5 (PPH5) is caused by homozygous or compound heterozygous mutation in the ATP13A3 gene (610232) on chromosome 3q29.
Primary pulmonary hypertension-5 (PPH5) is an autosomal recessive disorder characterized by the onset of pulmonary arterial hypertension in infancy, resulting in right heart dysfunction and ultimately right heart failure. Death in early childhood is common (Machado et al., 2022).
For a discussion of genetic heterogeneity of primary pulmonary hypertension, see PPH1 (178600).
Machado et al. (2022) reported 5 children from 3 unrelated families who were diagnosed with primary pulmonary arterial hypertension between 7 days and 2.5 years of age. Four of the patients died between 11 months and 8 years; the 8-year-old patient who died had undergone lung transplant at age 4.5 years. The patients presented with evidence of right ventricular (RV) dysfunction, RV dilatation and hypertrophy, and increased RV pressure. Some had cyanosis and respiratory distress. Despite treatment, the disorder resulted in right heart failure. One patient (family 3) underwent successful Potts shunt and was still alive with much improved exercise intolerance.
The transmission pattern of PPH5 in the families reported by Machado et al. (2022) was consistent with autosomal recessive inheritance.
Barozzi et al. (2019) identified a homozygous missense mutation (V855M; 610232.0001) in the ATP13A3 gene in a boy of European origin with PPH5. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family (family 15). Clinical details were limited, but the proband had an affected brother who died of the disease. Functional studies were not performed.
In 5 children from 3 unrelated families with PPH5, Machado et al. (2022) identified homozygous or compound heterozygous mutations in the ATP13A3 gene (610232.0001-610232.0005). The mutations segregated with the disorder in all families. There were missense, nonsense, and frameshift mutations. Functional studies of the variants and studies of patient cells were not performed, but the authors hypothesized that the ATP13A3 variants may alter transporter function and disturb polyamine homeostasis. The heterozygous parents, who were between 32 and 44 years of age, were unaffected.
Several reports have suggested autosomal inheritance of primary pulmonary hypertension. Coleman et al. (1959) observed primary pulmonary hypertension in 2 sisters and a brother and confirmed the diagnosis by postmortem examination. Tsagaris and Tikoff (1968) reported a family in which 3 sibs were affected: 2 males and 1 female. Hood et al. (1968) reported the condition in 3 sisters. Their review of the literature led them to conclude that single-generation cases tend to be predominantly in women and to have later onset than multiple-generation cases, which tend to show more equal sex distribution. Robertson et al. (1969) described 2 sisters, aged 26 and 22 years, with idiopathic pulmonary hypertension and reported the results of combined microangiographic and histologic studies of the intralobular arterial pattern in one.
Barozzi, C., Galletti, M., Tomasi, L., De Fanti, S., Palazzini, M., Manes, A., Sazzini, M., Galie, N. A combined targeted and whole exome sequencing approach identified novel candidate genes involved in heritable pulmonary arterial hypertension. Sci. Rep. 9: 753, 2019. [PubMed: 30679663] [Full Text: https://doi.org/10.1038/s41598-018-37277-0]
Coleman, P. N., Edmunds, A. W., Tregillus, J. Primary pulmonary hypertension in three sibs. Brit. Heart J. 21: 81-88, 1959. [PubMed: 13618464] [Full Text: https://doi.org/10.1136/hrt.21.1.81]
Hood, W. B., Jr., Spencer, H., Lass, R. W., Daley, R. Primary pulmonary hypertension: familial occurrence. Brit. Heart J. 30: 336-343, 1968. [PubMed: 5651246] [Full Text: https://doi.org/10.1136/hrt.30.3.336]
Machado, R. D., Welch, C. L., Haimel, M., Bleda, M., Colglazier, E., Coulson, J. D., Debeljak, M., Ekstein, J., Fineman, J. R., Golden, W. C., Griffin, E. L., Hadinnapola, C., and 11 others. Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality. J. Med. Genet. 59: 906-911, 2022. [PubMed: 34493544] [Full Text: https://doi.org/10.1136/jmedgenet-2021-107831]
Robertson, B., Rosenhamer, G., Lindberg, J. Idiopathic pulmonary hypertension in two siblings: clinical, microangiographic and histologic observations. Acta Med. Scand. 186: 569-577, 1969. [PubMed: 5382078] [Full Text: https://doi.org/10.1111/j.0954-6820.1969.tb01525.x]
Tsagaris, T. J., Tikoff, G. Familial primary pulmonary hypertension. Am. Rev. Resp. Dis. 97: 127-130, 1968.