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BRWD1 and Primary Ciliary Dyskinesia

Bi-allelic variants in BRWD1 have been identified in three unrelated individuals with autosomal recessive primary ciliary dyskinesia (PCD) and multiple morphological abnormalities of the sperm flagella (MMAF). Exome sequencing of 53 patients with MMAF plus respiratory symptoms uncovered two homozygous missense variants and one compound-heterozygous missense variant in BRWD1, including c.5573A>T (p.Gln1858Leu) (PMID:33389130). All three unrelated probands (PMID:33389130) exhibited chronic sinusitis (HP:0011109) and bronchiectasis (HP:0002110), consistent with PCD, with no additional segregating affected relatives reported.

Functional studies demonstrated absence of BRWD1 protein in patient respiratory cilia and sperm flagella, with transmission electron microscopy revealing loss of inner and outer dynein arms in both tissues and microtubule doublet defects in respiratory cilia. A mouse Brwd1 loss-of-function model recapitulated oligoasthenoteratospermia and infertility, supporting a loss-of-function mechanism in ciliogenesis and spermiogenesis (PMID:33389130; PMID:18353305).

Key Take-home: BRWD1 should be included in genetic testing panels for autosomal recessive PCD and related ciliopathies.

References

  • Human genetics • 2021 • Bi-allelic BRWD1 variants cause male infertility with asthenoteratozoospermia and likely primary ciliary dyskinesia. PMID:33389130
  • Developmental biology • 2008 • The dual bromodomain and WD repeat-containing mouse protein BRWD1 is required for normal spermiogenesis and the oocyte-embryo transition. PMID:18353305

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Three unrelated probands (PMID:33389130) with bi-allelic BRWD1 variants and concordant functional data

Genetic Evidence

Moderate

Identification of biallelic missense variants in three probands with PCD-like respiratory and sperm flagellar phenotypes (PMID:33389130)

Functional Evidence

Moderate

Absence of BRWD1 in patient cilia with dynein arm defects, and Brwd1 mouse model recapitulates spermiogenesis and ciliary dysfunction (PMID:33389130; PMID:18353305)