Highlighted Publications

This month’s highlighted publication, led by Professor Bill Newman from Manchester University NHS Foundation Trust (MFT) and The University of Manchester, identifies novel genetic variants responsible for Perrault syndrome, a rare genetic disorder characterized primarily by sensorineural hearing loss and ovarian insufficiency. Published in the American Journal of Human Genetics, the international collaborative studies pinpoint pathogenic mutations in two mitochondrial-related genes—DAP3 and MRPL49—that significantly expand the known genetic basis of this syndrome.

The researchers demonstrated that biallelic variants in DAP3 result in impaired assembly of the mitochondrial ribosomal small subunit, leading to altered mitochondrial function and increased apoptosis. Patients with DAP3 mutations exhibited hearing loss, ovarian dysfunction, and neurological features, confirming the gene’s critical role in disease pathogenesis. Similarly, variants in MRPL49 were associated with sensorineural hearing loss, ovarian insufficiency, and additional neurological symptoms, including leukodystrophy, highlighting a broader phenotypic spectrum than previously understood.

These findings significantly enhance diagnostic capabilities, providing molecular confirmation in cases previously undiagnosed by genetic testing. Funded by the NIHR Manchester Biomedical Research Centre (BRC), Action Medical Research, RNID, and the Medical Research Council, this research facilitates earlier diagnosis, tailored genetic counselling, and the potential development of targeted therapeutic strategies for patients worldwide.

References:

1. Smith TB, Kopajtich R, Demain LAM, Rea A, Thomas HB, Schiff M, Beetz C, Joss S, Conway GS, Shukla A, Yeole M, Radhakrishnan P, Azzouz H, Ben Chehida A, Elmaleh-Bergès M, Glasgow RIC, Thompson K, Oláhová M, He L, Jenkinson EM, Jahic A, Belyantseva IA, Barzik M, Urquhart JE, O’Sullivan J, Williams SG, Bhaskar SS, Carrera S, Blakes AJM, Banka S, Yue WW, Ellingford JM, Houlden H; DDD Study; Munro KJ, Friedman TB, Taylor RW, Prokisch H, O’Keefe RT, Newman WG. Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype. Am J Hum Genet. 2025 Jan 2;112(1):59-74. doi: 10.1016/j.ajhg.2024.11.007. Epub 2024 Dec 18. PMID: 39701103; PMCID: PMC11739875.

Link to article

2. Thomas HB, Demain LAM, Cabrera-Orefice A, Schrauwen I, Shamseldin HE, Rea A, Bharadwaj T, Smith TB, Oláhová M, Thompson K, He L, Kaur N, Shukla A, Abukhalid M, Ansar M, Rehman S, Riazuddin S, Abdulwahab F, Smith JM, Stark Z, Mancilar H, Tumer S, Esen FN, Uctepe E, Topcu V, Yesilyurt A, Afzal E, Salari M, Carroll C, Zifarelli G, Bauer P, Kor D, Bulut FD, Houlden H, Maroofian R, Carrera S, Yue WW, Munro KJ, Alkuraya FS, Jamieson P, Ahmed ZM, Leal SM, Taylor RW, Wittig I, O’Keefe RT, Newman WG. Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency. Am J Hum Genet. 2025 Feb 25:S0002-9297(25)00053-9. doi: 10.1016/j.ajhg.2025.02.005. Epub ahead of print. PMID: 40043708.

Link to article