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Combined exome and whole transcriptome sequencing identifies a de novo intronic SRCAP variant causing DEHMBA syndrome with severe sleep disorder

Journal of Human Genetics (2024)Cite this article

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Abstract

Rare heterozygous variants in exons 33-34 of the SRCAP gene are associated with Floating-Harbor syndrome and have a dominant-negative mechanism of action. At variance, heterozygous null alleles falling in other parts of the same gene cause developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) syndrome. We report an 18-year-old man with DEHMBA syndrome and obstructive sleep apnea, who underwent exome sequencing (ES) and whole transcriptome sequencing (WTS) on peripheral blood. Trio analysis prioritized the de novo heterozygous c.5658+5 G > A variant. WTS promptly demostrated four different abnormal transcripts affecting >40% of the reads, three of which leading to a frameshift. This study demonstrated the efficacy of a combined ES-WTS approach in solving undiagnosed cases. We also speculated that sleep respiratory disorder may be an underdiagnosed complication of DEHMBA syndrome.

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Acknowledgements

We thank the family for their availability in the study. This work was supported by the Ricerca Corrente 2022-2024 and Ricerca Finalizzata (RF_2021_12373524) from the Italian Ministry of Health to MC and DC; Fondazione Telethon Core Grant, Armenise-Harvard Foundation Career Development Award, European Research Council (grant agreement 759154, CellKarma), Italian Ministry of Health (Piano Operativo Salute Traiettoria 3, “Genomed”) to DC. MC, SM, and RPO recruited the clinical case. LM, DC, SM, and MC conceived and designed the work that led to the submission, acquired data, and played an important role in interpreting the results. MPL, LB, and LM analysed the exome-sequencing data. LV and DC analysed the RNA sequencing data. GN, LV, and LM performed the molecular studies. SM, MC, LM, LV wrote the manuscript. All authors agreed to be accountable for all aspects of the work. All authors revised and approved the final manuscript.

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Author notes

  1. These authors contributed equally: Silvia Morlino, Lorenzo Vaccaro.

  2. These authors jointly supervised this work: Davide Cacchiarelli, Lucia Micale.

Authors and Affiliations

  1. Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, Viale Cappuccini snc, 71013, San Giovanni Rotondo, Foggia, Italy

    Silvia Morlino, Maria Pia Leone, Grazia Nardella, Luigi Bisceglia, Marco Castori & Lucia Micale

  2. Armenise/Harvard Laboratory of Integrative Genomics, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy

    Lorenzo Vaccaro & Davide Cacchiarelli

  3. Department of Translational Medicine, University of Naples “Federico II”, Naples, Italy

    Lorenzo Vaccaro & Davide Cacchiarelli

  4. Division of Maxillofacial Surgery and Otolaryngology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013, Foggia, Italy

    Rocco Pio Ortore, Giannandrea Verzicco & Lazzaro Cassano

  5. Genomics and Experimental Medicine Program, Scuola Superiore Meridionale, Naples, Italy

    Davide Cacchiarelli

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  1. Silvia Morlino
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Correspondence to Marco Castori.

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All authors declare that there is no conflict of interest concerning this work. DC is founder, shareholder, and consultant of NEGEDIA (Next Generation Diagnostic srl).

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Morlino, S., Vaccaro, L., Leone, M.P. et al. Combined exome and whole transcriptome sequencing identifies a de novo intronic SRCAP variant causing DEHMBA syndrome with severe sleep disorder. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01240-x

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