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Lethal neonatal respiratory failure due to biallelic variants in BBS1 and monoallelic variant in TTC21B

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Abstract

Background

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive ciliopathy characterized by early onset retinal dystrophy, renal anomalies, postaxial polydactyly, and cognitive impairment with considerable phenotypic heterogeneity. BBS results from biallelic pathogenic variants in over 20 genes that encode key proteins required for the assembly or primary ciliary functions of the BBSome, a heterooctameric protein complex critical for homeostasis of primary cilia. While variants in BBS1 are most frequently identified in affected individuals, the renal and pulmonary phenotypes associated with BBS1 variants are reportedly less severe than those seen in affected individuals with pathogenic variants in the other BBS-associated genes.

Case-Diagnosis

We report an infant with severe renal dysplasia and lethal pulmonary hypoplasia who was homozygous for the most common BBS1 pathogenic variant (c.1169 T > G; p.M390R) and also carried a predicted pathogenic variant in TTC21B (c.1846C > T; p.R616C), a genetic modifier of disease severity of ciliopathies associated with renal dysplasia and pulmonary hypoplasia.

Conclusions

This report expands the phenotypic spectrum of BBS with the first infant with lethal neonatal respiratory failure associated with biallelic, pathogenic variants in BBS1 and a monoallelic, predicted pathogenic variant in TTC21B. BBS should be considered among the ciliopathies in the differential diagnosis of neonates with renal dysplasia and severe respiratory failure.

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Data availability

Data sharing not applicable to this article as no datasets or analyses were generated during the current study.

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Funding

This work was supported by grants from the National Institutes of Health (U01 HL134745 (FSC, JAW), R01 HL149853 (JAW)) and the Children’s Discovery Institute (FSC, JAW).

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Authors and Affiliations

  1. Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MT, USA

    Luke Viehl, Daniel J. Wegner, Stanley P. Hmiel, F. S. Cole & Jennifer A. Wambach

  2. Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MT, USA

    Frances V. White

  3. John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, MT, USA

    Sanjay Jain

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  1. Luke Viehl
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  2. Daniel J. Wegner
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  3. Stanley P. Hmiel
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  6. F. S. Cole
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  7. Jennifer A. Wambach
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Corresponding author

Correspondence to Jennifer A. Wambach.

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This study was reviewed and approved by the Human Research Protection Office at Washington University School of Medicine. We obtained informed written consent from the parents for participation in this study and publication of the findings.

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The authors declare no competing interests.

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Viehl, L., Wegner, D.J., Hmiel, S.P. et al. Lethal neonatal respiratory failure due to biallelic variants in BBS1 and monoallelic variant in TTC21B. Pediatr Nephrol 38, 605–609 (2023). https://doi.org/10.1007/s00467-022-05616-z

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  • DOI: https://doi.org/10.1007/s00467-022-05616-z

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