Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome

Adrian Palencia-Campos; Phillip C Aoto; Erik MF Machal; Ana Rivera-Barahona; Patricia Soto-Bielicka; Daniela Bertinetti; Blaine Baker; Lily Vu; Francesca Piceci-Sparascio; Isabella Torrente; Eveline Boudin; Silke Peeters; Wim Van Hul; Celine Huber; Dominique Bonneau; Michael S Hildebrand; Matthew Coleman; Melanie Bahlo; Mark F Bennett; Amy L Schneider; Ingrid E Scheffer; Maria Kibaek; Britta S Kristiansen; Mahmoud Y Issa; Mennat Mehrez; Samira Ismail; Jair Tenorio; Gaoyang Li; Bjorn Steen Skalhegg; Ghada A Otaify; Samia Temtamy; Mona Aglan; Aia E Jonch; Alessandro De Luca; Geert Mortier; Valerie Cormier-Daire; Alban Ziegler; Mathew Wallis; Pablo Lapunzina; Friedrich W Herberg; Susan S Taylor; Victor L Ruiz-Perez

Journal article

Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome

Adrian Palencia-Campos, Phillip C Aoto, Erik MF Machal, Ana Rivera-Barahona, Patricia Soto-Bielicka, Daniela Bertinetti, Blaine Baker, Lily Vu, Francesca Piceci-Sparascio, Isabella Torrente, Eveline Boudin, Silke Peeters, Wim Van Hul, Celine Huber, Dominique Bonneau, Michael S Hildebrand, Matthew Coleman, Melanie Bahlo, Mark F Bennett, Amy L Schneider Show all

American Journal of Human Genetics | Elsevier (Cell Press) | Published : 2020

DOI: 10.1016/j.ajhg.2020.09.005

Abstract

PRKACA and PRKACB code for two catalytic subunits (Cα and Cβ) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their..

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University of Melbourne Researchers

Melanie Bahlo Author Mathematics and Statistics

Ingrid Scheffer Author Medicine - Austin Health

Michael Hildebrand Author Medicine - Austin Health

Mark Bennett Author Medical Biology (W.E.H.I.)

Amy Schneider Author Medicine - Austin Health

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Grants

Awarded by Spanish Ministry of Science, Innovation and Universities

Awarded by NIH

Awarded by University of Antwerp

Awarded by The ResearchFoundation Flanders

Awarded by National Health and Medical Research Council

Awarded by Throne Holst Foundation UiO

Funding Acknowledgements

We thank all affected individuals, their siblings, and their parents or legal guardians for their participation in this study. Some individuals were included after aGeneMatchermatch.40 This workwas partially supported by funding fromthe Spanish Ministry of Science, Innovation and Universities (SAF2016-75434-R [AEI/FEDER, UE] and PID2019-105620RB-I00/AEI/10.13039/501100011033) to V.L.R.-P. S.S.T. was supported byNIHgrant R03TR002947, E.M.F.M. by Kassel graduate school ``Clocks'', and A.D.L. by the Italian Ministry of Health (RC-2019). The University of Antwerp supported G.M. and W.V.H. with Methusalem funding (FFB190208) and S.P. with a predoctoral grant. E.B. was supported by The ResearchFoundation Flanders with a postdoctoral grant (12A3814N). The study was also funded by aNationalHealth andMedical ResearchCouncil Program Grant (1091593) to I.E.S., a Practitioner Fellowship (1006110) to I.E.S., a Senior Research Fellowship (1102971) to M.B., and an R.D. Wright Career Development Fellowship (1063799) to M.S.H. B.S.S. and G.L. were supported by Throne Holst Foundation UiO (20192021) and Strategic PhD fund by UiO/IMB.