A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-49 (CILD49) without situs inversus is caused by compound heterozygous mutation in the CFAP74 gene (620187) on chromosome 1p36.

Primary ciliary dyskinesia-49 (CILD49) without situs inversus is an autosomal recessive disorder characterized by the onset of recurrent respiratory infections, chronic cough, and bronchiectasis in early childhood due to defective ciliary clearance. Affected males also show infertility due to defective flagellar morphology and function. Nasal nitric oxide (NO) levels are normal and situs abnormalities are not observed (Sha et al., 2020; Biebach et al., 2022).

For a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Sha et al. (2020) reported 2 unrelated Chinese adult males with typical symptoms of primary ciliary dyskinesia, including chronic bronchiectasis, frequent sinusitis, and infertility. Both patients had a history of chronic coughing and expectoration throughout their childhoods. Analysis of patient sperm showed various tail defects; the flagella were short, bent, coiled, or abnormally wide compared to controls. Patient sperm showed an incomplete mitochondrial sheath, and cross-sections showed that the mitochondrial sheath was disorganized or absent and the outer dense fibers and doublet microtubules were randomly organized or inadequate. Due to the patients' infertility, one couple underwent intracytoplasmic sperm injection (ICSI), resulting in pregnancy after embryo transfer and the birth of a healthy baby. These findings indicated that the sperm flagella abnormalities did not affect fertilization or clinical pregnancy.

Biebach et al. (2022) reported 3 patients from 2 unrelated families with CILD49. Family OP-3882 consisted of 2 affected sibs: a 48-year-old male and his 57-year-old sister, both of whom had recurrent respiratory infections and chronic cough since childhood. Additional features included bronchiectasis and nasal polyposis. Neither sib had children. The only affected individual in the other family (OP-4027) was a 14-year-old boy with recurrent airway infections since infancy. He also had nasal polyposis and pansinusitis. Nasal NO production was normal in all, and all 3 individuals had normal situs composition (situs solitus). A sperm sample from the 48-year-old man in family OP-3882 showed oligoasthenospermia with reduced ejaculate volume and sperm concentration. The sperm were completely immotile. Sperm flagella showed multiple morphologic defects, including being short, coiled, bent, absent, or irregularly wide. Transmission electron microscopy showed a regular 9+2 ciliary ultrastructure without defects of the tubular structure and attached outer and inner dynein arms. High-speed video microscopy of patient respiratory epithelial cells showed a decreased ciliary beat frequency compared to controls, consistent with decreased ciliary clearance capacity.

The transmission pattern of CILD49 in the families reported by Sha et al. (2020) was consistent with autosomal recessive inheritance.

In 2 unrelated Chinese men with CILD49, Sha et al. (2020) identified compound heterozygous missense mutations in the CFAP74 gene (620187.0001-620187.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient sperm samples showed near absence of CFAP74 immunostaining in the flagella. The authors postulated that the mutations resulted in a loss-of-function effect, resulting in abnormal assembly of the axoneme structure.

In 3 patients from 2 unrelated families (OP-3882 and OP-4027) with CILD49, Biebach et al. (2022) identified compound heterozygous frameshift mutations in the CFAP74 gene (620187.0005-620187.0007). The mutations, which were found by sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in both families. Patient respiratory epithelial cells showed loss of CFAP74, consistent with a loss-of-function effect of the mutations.