Abstract
Cutis laxa is a highly heterogeneous connective tissue disorder characterized by progressively loose skin, often accompanied by systemic involvement. Autosomal dominant cutis laxa (ADCL) has been linked to variants in several genes, including ALDH18A1, which encodes Δ1-pyrroline-5-carboxylate synthetase, a key enzyme in proline and collagen metabolism. We report a novel case of ADCL in a 1.6-year-old patient presenting with growth delay, hypotonia, joint laxity, lax skin, cataract, dysmorphic features, microcephaly, cranial vessel tortuosity, hip dislocation, and psychomotor retardation. Whole-exome sequencing revealed a de novo heterozygous c.400 T > C (p.Ser134Pro) substitution in the ALDH18A1 gene. This variant has not been previously reported, and it is the first report of an individual with ALDH18A1-ADCL due to a substitution at a highly conserved residue, p.Ser134 of the P5CS protein. Our findings expand the mutational spectrum of ALDH18A1-related ADCL and highlight the importance of genetic testing in diagnosing rare disorders.
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Acknowledgements
We express our gratitude to the family for their involvement in this research. The authors are grateful to the management of Unipath Speciality Laboratory Limited, Ahmedabad, for providing the necessary infrastructure facilities.
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FA contributed to the study’s conception and design. PG, and NN, did the clinical evaluation. FA, PG, NN, SS, and NA wrote the main manuscript. MK, AS, and MA did the microarray analyses. FA, MA, PC, EJ, TV, AB, and SC, did the molecular experiments and data analysis. All authors reviewed the manuscript.
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The study is in accordance with the ethical standards of our institution and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Ahmad, F., Gadgil, P., Navandar, N. et al. A novel case of autosomal-dominant cutis laxa caused by a de novo likely pathogenic variant in ALDH18A1: case report and literature review. J Hum Genet 70, 325–329 (2025). https://doi.org/10.1038/s10038-025-01334-0
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DOI: https://doi.org/10.1038/s10038-025-01334-0
