Molecular characterization of FAM222B as a novel disease gene for dominant cardiovascular laterality defects

Reitz N, Lambertz J, Yilmaz Ö, Lindenberg TT, Channab K, Rau B, Ramrath S, Mingardo E, Schöpper H, Kirchmaier BC, Geyer M, Dworschak GC, Breuer J, Müller N, Schaidinger B, Hilger A, Hoefele J, Riedhammer KM, Hitz MP, Dombrowsky G, Abdul-Khaliq H, Bauer UM, Fester L, Reutter HM, Breuer K, Odermatt B (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Scientific Reports Nature Publishing Group: Open Access Journals - Option B

Book Volume: 16

Article Number: 26359

Journal Issue: 1

DOI: 10.1038/s41598-026-64853-6

Abstract

Cardiovascular laterality defects occur with an estimated birth prevalence of 1.1/10,000 live births, associated with congenital heart defects (CHD) and situs abnormalities. Known disease genes explain about 20% of all cases often correlated with primary ciliary dyskinesia (PCD). We aimed to identify disease genes beyond PCD-related aetiologies using exome sequencing in 16 case-parent trios followed by exome survey in 2,109 individuals with situs inversus totalis, heterotaxy, or isolated CHD. We identified six different variants in FAM222B, previously discussed as a candidate gene for cerebral cavernous malformations. The variant c.899G > A (p.300Arg > His) was found de novo in two unrelated families. FAM222B has been described as a substrate of Nemo-like kinase (NLK), associated with left–right body axis determination. Structural modelling suggests a function of FAM222B Arg300 in NLK recognition. We investigated whole-mount in situ hybridization (WISH) expression pattern and genomic context of the zebrafish (zf) FAM222B homologues, fam222ba/bb, and fam222aa. Using a double-knockout (dd-KO) fam222ba/bb zf line, we identified aberrant cardiac looping in these larvae and enlarged atrium and ventricle in adult zf. We further tested the c.899G > A variant using human mRNA injections in Tg(kdrl:EGFP) wildtype (wt) reporter-zf, which led to perturbed cardiogenesis. Together, we propose FAM222B as a novel candidate gene for cardiovascular laterality defects.

Authors with CRIS profile

Alina Hilger Department of Paediatrics and Adolescent Medicine Heiko Martin Reutter Professur für Neonatologie

Involved external institutions

Altonaer Kinderkrankenhaus (AKK) DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Carl von Ossietzky Universität Oldenburg DE Germany (DE) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Competence Network for Congenital Heart Defects DE Germany (DE) Goethe-Universität Frankfurt am Main DE Germany (DE) Universitätsklinikum Bonn DE Germany (DE) Klinikum der Universität München (LMU Klinikum) DE Germany (DE)

How to cite

APA:

Reitz, N., Lambertz, J., Yilmaz, Ö., Lindenberg, T.T., Channab, K., Rau, B.,... Odermatt, B. (2026). Molecular characterization of FAM222B as a novel disease gene for dominant cardiovascular laterality defects. Scientific Reports, 16(1). https://doi.org/10.1038/s41598-026-64853-6

MLA:

Reitz, Nina, et al. "Molecular characterization of FAM222B as a novel disease gene for dominant cardiovascular laterality defects." Scientific Reports 16.1 (2026).

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