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Beecroft SJ, Ayala M, McGillivray G, et al. Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects. Hum Mutat. 2021;42(5):506-519doi: 10.1002/humu.24179.
Beecroft, S. J., Ayala, M., McGillivray, G., Nanda, V., Agolini, E., Novelli, A., Digilio, M. C., Dotta, A., Carrozzo, R., Clayton, J., Gaffney, L., McLean, C. A., Ng, J., Laing, N. G., Matteson, P., Millonig, J., & Ravenscroft, G. (2021). Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects. Human mutation, 42(5), 506-519. https://doi.org/10.1002/humu.24179
Beecroft, Sarah J, et al. "Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects." Human mutation vol. 42,5 (2021): 506-519. doi: https://doi.org/10.1002/humu.24179
Beecroft SJ, Ayala M, McGillivray G, Nanda V, Agolini E, Novelli A, Digilio MC, Dotta A, Carrozzo R, Clayton J, Gaffney L, McLean CA, Ng J, Laing NG, Matteson P, Millonig J, Ravenscroft G. Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects. Hum Mutat. 2021 May;42(5):506-519. doi: 10.1002/humu.24179. Epub 2021 Apr 01. PMID: 33565183.
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Hum Mutat. 2021 May;42(5):506-519. doi: 10.1002/humu.24179. Epub 2021 Apr 01.

Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects.

Human mutation

Sarah J Beecroft, Marcos Ayala, George McGillivray, Vikas Nanda, Emanuele Agolini, Antonio Novelli, Maria C Digilio, Andrea Dotta, Rosalba Carrozzo, Joshua Clayton, Lydia Gaffney, Catriona A McLean, Jessica Ng, Nigel G Laing, Paul Matteson, James Millonig, Gianina Ravenscroft

Affiliations

  1. Faculty of Health and Medical Sciences, Centre of Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
  2. Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, USA.
  3. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Women's Hospital, Melbourne, Australia.
  4. Department of Biochemistry and Molecular Biology, Center for Advanced Biotechnology and Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.
  5. Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, Rome, Italy.
  6. Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  7. Division of Newborn Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  8. Unit of Muscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy.
  9. Anatomical Pathology and Victorian Neuromuscular Laboratory Service, Alfred Health and Monash University, Melbourne, Victoria, Australia.
  10. Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Australia.
  11. Department of Neuroscience and Cell Biology, Center for Advanced Biotechnology and Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.

PMID: 33565183 DOI: 10.1002/humu.24179

Abstract

This study shows a causal association between ALDH1A2 variants and a novel, severe multiple congenital anomaly syndrome in humans that is neonatally lethal due to associated pulmonary hypoplasia and respiratory failure. In two families, exome sequencing identified compound heterozygous missense variants in ALDH1A2. ALDH1A2 is involved in the conversion of retinol (vitamin A) into retinoic acid (RA), which is an essential regulator of diaphragm and cardiovascular formation during embryogenesis. Reduced RA causes cardiovascular, diaphragmatic, and associated pulmonary defects in several animal models, matching the phenotype observed in our patients. In silico protein modeling showed probable impairment of ALDH1A2 for three of the four substitutions. In vitro studies show a reduction of RA. Few pathogenic variants in genes encoding components of the retinoic signaling pathway have been described to date, likely due to embryonic lethality. Thus, this study contributes significantly to knowledge of the role of this pathway in human diaphragm and cardiovascular development and disease. Some clinical features in our patients are also observed in Fryns syndrome (MIM# 229850), syndromic microphthalmia 9 (MIM# 601186), and DiGeorge syndrome (MIM# 188400). Patients with similar clinical features who are genetically undiagnosed should be tested for recessive ALDH1A2-deficient malformation syndrome.

© 2021 Wiley Periodicals LLC.

Keywords: ALDH1A2; congenital heart defects; diaphragmatic defects; fetal development; genetics; respiratory defects; retinoic acid

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