Identification and Characterization of a Rare Exon 22 Duplication in CFTR in Two Families

Ahting, Simone; Henn, Constance; vom Hove, Maike; Strehlow, Vincent; Duffek, Patricia; Behrendt, Sophie; Drukewitz, Stephan; Berger, Jasmin; Graeber, Simon Y.; Hentschel, Julia

doi:10.3390/ijms26104487

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Identification and Characterization of a Rare Exon 22 Duplication in CFTR in Two Families

by

Simone Ahting

¹,

Constance Henn

²,

Maike vom Hove

³,

Vincent Strehlow

¹,

Patricia Duffek

¹,

Sophie Behrendt

¹,

Stephan Drukewitz

¹,

Jasmin Berger

^4,5,

Simon Y. Graeber

^4,5

and

Julia Hentschel

^1,*

¹

Institute of Human Genetics, University Hospital Leipzig, 04103 Leipzig, Germany

²

Pediatricians Office Dr. Henn, Pediatric Pulmonology, 04177 Leipzig, Germany

³

Division of Pediatric Pulmonology and Allergology, Hospital for Children and Adolescents, University Medical Center Leipzig, 04103 Leipzig, Germany

⁴

Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany

⁵

German Center for Lung Research, Associated Partner Site, 13353 Berlin, Germany

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(10), 4487; https://doi.org/10.3390/ijms26104487

Submission received: 14 March 2025 / Revised: 30 April 2025 / Accepted: 6 May 2025 / Published: 8 May 2025

(This article belongs to the Special Issue Genomic Variation and Epidemiology of Cystic Fibrosis)

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Abstract

Accurate genetic diagnosis is essential for appropriate treatment in cystic fibrosis (CF). Large copy number variants like duplications in the CFTR gene are rare and often classified as variants of uncertain significance (VUSs) due to unknown characteristics of the inserted material, complicating diagnosis and treatment decisions. We identified a previously uncharacterized exon 22 duplication (CFTRdup22) in the CFTR gene in two anamnestically unrelated people with CF, both exhibiting a mild phenotype. Initial classification as a VUS was based on standard genetic testing. We employed a custom next-generation sequencing (NGS) panel to determine the exact breakpoints of the duplication and conducted mRNA sequencing to confirm its effect on splicing. DNA and RNA analyses allowed for precise breakpoint determination, confirming that the duplication was in tandem and the reading frame remained intact. This, as well as a residual CFTRdup22 function of ~30% as measured via intestinal current measurement, is consistent with a clinically milder CF phenotype. Collectively, the precise characterization of the variants’ breakpoints, localization and orientation enabled us to reclassify the variant as likely pathogenic. This study highlights the importance of advanced genetic techniques, such as NGS and breakpoint analysis, in accurately identifying CF-causing variants. It underscores the importance of a comprehensive approach and persistence when suspecting a specific genetic condition. This can aid in reclassifying VUSs, providing a definitive diagnosis for the affected family and enabling appropriate therapeutic interventions, including the use of CFTR modulators.

Keywords: NGS; cystic fibrosis; RNA sequencing; genetic diagnostics; breakpoint analysis

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MDPI and ACS Style

Ahting, S.; Henn, C.; vom Hove, M.; Strehlow, V.; Duffek, P.; Behrendt, S.; Drukewitz, S.; Berger, J.; Graeber, S.Y.; Hentschel, J. Identification and Characterization of a Rare Exon 22 Duplication in CFTR in Two Families. Int. J. Mol. Sci. 2025, 26, 4487. https://doi.org/10.3390/ijms26104487

AMA Style

Ahting S, Henn C, vom Hove M, Strehlow V, Duffek P, Behrendt S, Drukewitz S, Berger J, Graeber SY, Hentschel J. Identification and Characterization of a Rare Exon 22 Duplication in CFTR in Two Families. International Journal of Molecular Sciences. 2025; 26(10):4487. https://doi.org/10.3390/ijms26104487

Chicago/Turabian Style

Ahting, Simone, Constance Henn, Maike vom Hove, Vincent Strehlow, Patricia Duffek, Sophie Behrendt, Stephan Drukewitz, Jasmin Berger, Simon Y. Graeber, and Julia Hentschel. 2025. "Identification and Characterization of a Rare Exon 22 Duplication in CFTR in Two Families" International Journal of Molecular Sciences 26, no. 10: 4487. https://doi.org/10.3390/ijms26104487

APA Style

Ahting, S., Henn, C., vom Hove, M., Strehlow, V., Duffek, P., Behrendt, S., Drukewitz, S., Berger, J., Graeber, S. Y., & Hentschel, J. (2025). Identification and Characterization of a Rare Exon 22 Duplication in CFTR in Two Families. International Journal of Molecular Sciences, 26(10), 4487. https://doi.org/10.3390/ijms26104487

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Identification and Characterization of a Rare Exon 22 Duplication in CFTR in Two Families

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