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Deletion of the last two exons of FGF10 in a family with LADD syndrome and pulmonary acinar hypoplasia

European Journal of Human Genetics volume 30, pages 480–484 (2022)Cite this article

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Abstract

Pulmonary acinar hypoplasia (PAH) and lacrimo-auriculo-dento-digital (LADD) syndrome have both been associated with loss-of-function variants in, or deletions of FGF10. Here we report a multi-generational family with seven members manifesting varying features of LADD syndrome, with one individual dying in early infancy of PAH. Whole genome sequencing in one family member identified a 12,158 bp deletion on chromosome 5p12 that removes two of the three exons of FGF10. Allele-specific PCR demonstrated that all affected family members, including the individual with PAH, carried the 12 kb deletion. We conclude the deletion is pathogenic and expands the mutational spectrum of FGF10 variants in LADD syndrome. The common mechanism underlying the variable clinical features of LADD syndrome is defective terminal branching of salivary and lacrimal glands and pulmonary acini, regulated by the TBX4-FGF10-FGFR2 pathway. The variable phenotypic expressivity of FGF10 haploinsufficiency from relatively benign to lethal is likely due to variation at other genetic loci.

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Fig. 1: Clinical findings in the affected family.
Fig. 2: Genetic findings in the affected family.

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Acknowledgements

We would like to thank the family for their support of this research, Dianne Webster, Stella Lai and Mark Greenslade at LabPlus, Auckland City Hospital for their help in extracting DNA from the Guthrie card sample, and Curekids for funding. This work was supported by CureKids, NZ.

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Authors and Affiliations

  1. Department of Women’s and Children’s Health, Otago Medical School, University of Otago, Dunedin, Aotearoa, New Zealand

    Emma M. Wade, Padmini Parthasarathy, Jingyi Mi, Tim Morgan & Stephen P. Robertson

  2. Institute of Human Genetics, University Medical Center, University of Göttingen, Göttingen, Germany

    Bernd Wollnik

  3. Department of Medicine, University of Auckland, Auckland, Aotearoa, New Zealand

    Tim Cundy

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  1. Emma M. Wade
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  2. Padmini Parthasarathy
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Correspondence to Emma M. Wade.

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Wade, E.M., Parthasarathy, P., Mi, J. et al. Deletion of the last two exons of FGF10 in a family with LADD syndrome and pulmonary acinar hypoplasia. Eur J Hum Genet 30, 480–484 (2022). https://doi.org/10.1038/s41431-021-00902-0

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