Clinical and genetic analysis of two patients with primary ciliary dyskinesia caused by a novel variant of DNAAF2

In this study, two compound heterozygous variants of DNAAF2 were identified in two siblings with similar PCD characteristics, including recurrent pneumonia dominated by the right middle and left lingular lobes with atelectasis, early bronchiectasis, sinusitis, otitis media, and significantly reduced nNO levels. One of the variants is the nonsense variant of NM_018139: c.156 C > A (p.Y52*), which has already been reported in a Chinese family and proved to be pathogenic [10]. Another variant is the frameshift variant (NM_018139: c.177_178insA (p.E60fs*3), which is a novel variant.

DNAAF2 is located on chromosome 14q21.3 and consists of three exons encoding cDNAs [10]. The variant p.E60fs*3 is located in exon1, near another variant p.Y52*. Exon1 is consists of 621 amino acids, and E60fs*3 variant leads to early transcription termination after 63 amino acids (Fig. 5). According to the standards and guidelines of American College of Medical Genetics and Genomics (ACMG), the frameshift variant p.E60fs*3 variant was pathogenic. In addition, none of cystic fibrosis (CF) or primary immune deficiency (PID) related genes were detected, which may also lead to recurrent pneumonia, atelectasis and bronchiectasis. Based on the clinical manifestations and hereditary mode of compound heterozygous variants from both parents, it is reasonable to consider that the novel p.E60fs*3 variant of DNAAF2 is responsible for the pathogenesis of PCD.

Over 50 genes have been reported to be associated with PCD, including DNAH5, DNAH11, DNAI1, DNAI2, DNAL1, TXNDC3, DNAAF1, DNAAF2, etc. [1, 6, 11]. In 2008, two heterozygous variants c.C23A [pS8X] and c.1214-1215insACGATACCTGCGTGGC [p.G406Rfs89X] variants of DNAAF2 were first identified in two consanguineous families with PCD presented with recurrent respiratory tract infections, laterality defects and impaired fertility [6]. DNAAF2 functions as a facilitator of dynein pre-assembly. The dysfunction of DNAAF2 is associated with the specific defects of the interaction between intermediate and heavy chains in the cytoplasm, leading to complete or partial loss of ODAs and IDAs and loss of motility [6]. Since then, only 14 PCD cases have been reported to be caused by DNAAF2 with 17 variants. The cases of DNAAF2 variant are summarized in Table 1 and variants on protein level are illustrated in Fig. 5 [6, 10, 12‐24]. DNAAF2 gene is rare for Chinese Children. As reported by Guan et al. in 81 Chinese children, the genes causing the highest variant rate of PCD was DNAH11, followed by HYDIN, DNAH5, CCDC39, DNAH1 and CCNO, no variant of DNAAF2 gene was detected [25]. In Chinese adult patients, Sun et.at have identified two heterozygous variants, c.C156A [p.Y52X] and c.C26A [p.S9X], in the DNAAF2 gene, leading to defects in the outer dynein arms and inner dynein arms, thereby resulting in PCD with the manifestation of male infertility [10]. Lu C et al. detected another two heterozygous variants, c.491T > C [p.L164P] and c.822del [p.A275Profs*10], in two females with bronchiectasis, sinusitis, situs inversus, and infertility. In addition, one woman with c.491T > C variant had scoliosis [24].

Consequently, we made an early diagnosis of PCD in two siblings with a rare novel variant of DNAAF2 gene. Early PCD may be easily misdiagnosed as common pneumonia or sinusitis. PCD should be considered when a child presented with recurrent pneumonia or atelectasis accompanied with recurrent sinusitis or otitis media. The characteristic HRCT manifestations include right middle and left lingular atelectasis, thickened bronchial wall, and mild bronchiectasis, which can provide a diagnostic clue for PCD. Moreover, the decrease of nNO is conducive to the further diagnosis, and genetic tests is conducive to confirming the diagnosis. TEM of bronchial cilia is also helpful for the diagnosis of PCD.