This mutation produced a premature stop codon at amino acid 1134, thus reducing the final protein size by 39 amino acids (total size 1174 amino acids). and pathological status. This study highlights the difficulties of identifying disease-causing variants for a highly heterogeneous disorder and reports on the identification of a novel variant in which recently associated with PCD. gene located on chromosome 3p24.1. Case presentation Two siblings from a Saudi consanguineous family were presented to our practice. Their parents were first-degree consanguineous couple with two additional healthy children and previous history of terminated pregnancy at 5th months of gestation by intrauterine fetal death (Fig.?1a). Both affected siblings underwent a carful clinical evaluation by a pulmonologist, immunologist, and clinical geneticist. Open in a separate window Fig. 1 a Pedigree of the family showing consanguineous union and recessive inheritance pattern. b Chest X-ray of the affected individual (IV-4) revealed bilateral para-cardiac patchy infiltration with blunting of the left CP angle. c, d CT scan for affected individuals (IV-3) & (IV-4) showing mediastinal lymph nodes enlargement and bronchiectasis changes involving left lower lobe/ lingual, right upper lobe, and lateral segment of middle and medial segment of right lower lobes. White arrows depicting bronchiectasis (c, d), while the black arrow shows mosaic appearance (c) The proband is usually a 5?years old girl (IV-4) born at full term by normal vaginal delivery. At 2?months of age, she developed recurrent presumed viral associated wheezing. She required hospitalization as she developed an increase in the severity of her respiratory episodes associated with hypoxia which need prolonged admission courses. She continued to have a chronic wet cough, recurrent otitis media, experienced multiple admissions for respiratory exacerbation. Once she was admitted to an intensive care unit, where she required non-invasive positive pressure ventilation and bronchodilator therapy and later discharged on oxygen at home. Developmentally, all her millstone domains were appropriate for her age. No other neurological or renal symptoms were observed. On examination, her excess weight was 13.5?kg (10th centile), height 98?cm (25th centile) and her head circumference 50?cm (between 50thC75th centile). Auscultation for her chest revealed an equal bilateral coarse breath sounds with diffuses crackles, while all other systemic examinations were unremarkable. A milder phenotype noticed in her elder 8?years old brother (IV-3) who also did not require admission, therefore CT chest requested confirmed bronchiectasis. The patient (IV-4) chest X-ray exhibited bilateral para-cardiac patchy infiltration with blunting of the left CP angle. (Fig. ?(Fig.1b).1b). CT chest for (IV-3, IV-4) showed bronchiectasis changes including lower lobes, right middle and lingula with hilar and mediastinal lymph nodes enlargement (Fig. ?(Fig.1c,d).1c,d). Upper GI study demonstrates moderate gastroesophageal reflux, without evidence of pulmonary aspiration, or evidence of tracheoesophageal fistula (TEF). Sweat chloride test revealed 20?mmol/L (40?mmol/L), Total IgE 15.90 KU/L (5C22 KU/L). P-ANCA and C-ANCA were 2.30 Units and 2.39 Models respectively ( ?20 unfavorable). Lymphocyte subsets, immunoglobulins, specific NVP-CGM097 antibody titers, oxidative NVP-CGM097 burst test, and total match activity (CH50) were all unremarkable.. Bronchoscopy showed normal airway anatomy with scattered solid whitish secretion bronchoalveolar lavage (BAL) taken and cultures were unfavorable for bacterial, fungal and mycobacterium. Laparoscopic lung biopsy revealed histiocytic, lymphoplasmacytic infiltrate and lymphoid aggregates, no evidence of granuloma or malignancy was NVP-CGM097 observed. Due to technical issues and limited resources, we could not perform ciliary EM, nasal nitric oxide (nNO), ciliary high-speed video microscopy (HSVM), ciliary beat pattern (CBP) and frequency (CBF). The present family was subjected to Whole Exome Sequencing (WES) using standard methods [15]. Step-by-step filtering and validation of different homozygous and compound heterozygous variants revealed a nonsense variant (c.3402?T? ?A); p.(Tyr1134*) in the exon 37 of the gene (“type”:”entrez-nucleotide”,”attrs”:”text”:”NM_152534.4″,”term_id”:”749385077″,”term_text”:”NM_152534.4″NM_152534.4; “type”:”entrez-protein”,”attrs”:”text”:”NP_955379.2″,”term_id”:”207029299″,”term_text”:”NP_955379.2″NP_955379.2). Using Sanger sequencing, the recognized variant segregated perfectly with the disease phenotype within the family. The variant was present in the heterozygous state in the obligate service providers of the families. FLT4 To exclude the non-pathogenic nature of the recognized variant, it was screened within 2000 Saudi exomes, ExAC and gnomAD databases. The pathogenicity index was calculated using different online analysis tools [(MutationTaster: Disease causing, FATHMM-MKL: Damaging, Varsome: PM2, PP3, DANN: 0.9924)] and was predicted disease causing..