Submission Details

BRWD1, Primary Ciliary Dyskinesia (MONDO:0016575), autosomal recessive

Primary Ciliary Dyskinesia (PCD) is a motile ciliopathy characterized by respiratory tract infections, body laterality defects and could be associated with infertility. Mutations in PCD patients have been identified in a heterogeneous group of genes normally expressed in cilia and/or sperm flagella (PMID: 33279404).
The BRWD1 gene was first reported in association with PCD in 2021 (PMID:33389130). A prior study published in 2015 (PMID: 26301565) reported patients with BRWD1 mutations, however, in association with a different pathology; autosomal dominant Agammaglobulinemia with incomplete penetrance (MONDO:0015977). Per criteria outlined by the ClinGen Lumping and Splitting Working Group and due to the differences in molecular mechanism and inheritance patterns, and the obvious phenotypic variability, the ClinGen Motile Ciliopathy GCEP working group estimated that PCD (MONDO: 0016575) and Agammaglobulinemia (MONDO:0015977) represent distinct diseases and decided to split the entities. BRWD1 is a protein containing 8 WD repeats and 2 bromodomains. While WD repeats have diverse functions (PMID: 11814058), the bromodomains are particularly involved in histone recognition (PMID: 22464331). The gene encoding the BRWD1 protein is located in the Down Syndrome critical region of chromosome 21 which shows conserved synteny with the mouse chromosome 16. Evidence from 3 probands reported in only one publication (PMID:33389130) were included in this curation representing 4 unique missense variants. There are no additional cases of PCD with *BRWD1 *mutations in the literature, therefore we reached only 0.7 points for the genetic evidence of this curation.
Generally, PCD-related genes are particularly expressed in ciliated epithelia and sperm flagella. This expression pattern is different for *BRWD1 *which is ubiquitously expressed in human tissues (PMID: 25613900). Thus, the score of this experimental evidence was downgraded to 0 (zero). The nuclear localization of BRWD1 is supported by abundant experimental evidence (PMID: 26301565, PMID: 25547156, PMID: 12889071). Besides immunostaining, coimmunoprecipitation showed that BRWD1 associates with BRG1 which is a component of a chromatin remodeling complex (PMID: 12889071). This contradicts the prediction of a ciliary expression of BRWD1 that would support this gene-disease relationship. Brwd1 mutated mice were generated through Ethylnitrosourea (ENU) mutagenesis. In these mice, the generated splice mutation causes the skipping of the exon 10 and leads to the expression of a truncated BRWD1 protein (PMID: 25547156). All the generated mice are infertile. In female mutated mice, in vitro maturation and insemination showed impaired oocyte-to-embryo transition. Only 44% of mutant oocytes progressed to Metaphase II (vs.94% in WT) and the rest were all arrested at the two pronuclear stage. Male mutated mice showed oligoasthenozoospermia and MMAF which resembles the phenotype observed in patients with BRWD1 mutations (PMID:33389130). Further investigations have shown that BRWD1 promotes haploid spermatid–specific transcription during postmeiotic sperm differentiation in male mice and is essential for epigenetic control of meiotic chromosome stability in females (PMID: 25547156). In mice, the loss of BRWD1 function interferes with the completion of oogenesis and spermatogenesis through sexually dimorphic mechanisms. By contrast to PCD patients, ciliary and/or flagellar structural defects may not be the main cause for the infertility in these mice. Moreover, no respiratory signs were reported in Brwd1 mutated mice. In summary, the evidence supporting the relationship between BRWD1 and autosomal recessive PCD has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role BRWD1 plays in this disease. This classification was approved by the ClinGen Motile Ciliopathy GCEP on November 10, 2022 (SOP Version 9).