Mutations in TP73 cause impaired mucociliary clearance and lissencephaly.

TP73 belongs to the TP53 family of transcription factors and has therefore been well studied in cancer research. Studies in mice, however, have revealed non-oncogenic activities related to multiciliogenesis. Utilizing whole-exome sequencing analysis in a cohort of individuals with a mucociliary clearance disorder and cortical malformation, we identified homozygous loss-of-function variants in TP73 in seven individuals from five unrelated families. All affected individuals exhibit a chronic airway disease as well as a brain malformation consistent with lissencephaly. We performed high-speed video microscopy, immunofluorescence analyses, and transmission electron microscopy in respiratory epithelial cells after spheroid or air liquid interface culture to analyze ciliary function, ciliary length, and number of multiciliated cells (MCCs). The respiratory epithelial cells studied display reduced ciliary length and basal bodies mislocalized within the cytoplasm. The number of MCCs is severely reduced, consistent with a reduced number of cells expressing the transcription factors crucial for multiciliogenesis (FOXJ1, RFX2). Our data demonstrate that autosomal-recessive deleterious variants in the TP53 family member TP73 cause a mucociliary clearance disorder due to a defect in MCC differentiation.

An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia.

Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients with a clinical suspicion of PCD but for whom no nasal nitric oxide test or ciliary functional assessment could be ordered. Among 81 patients (56 families), in whom PCD was suspected, 68% had pathogenic or likely pathogenic variants in established PCD-related genes that fully explain the phenotype (20 variants in 11 genes). The major clinical presentations were sinopulmonary infections (SPI) (n = 58), neonatal respiratory distress (NRD) (n = 2), laterality defect (LD) (n = 6), and combined LD/SPI (n = 15). Biallelic likely deleterious variants were also encountered in AKNA and GOLGA3, which we propose as novel candidates in a lung phenotype that overlaps clinically with PCD. We also encountered a PCD phenocopy caused by a pathogenic variant in ITCH, and a pathogenic variant in CEP164 causing Bardet-Biedl syndrome and PCD presentation as a very rare example of the dual presentation of these two disorders of the primary and motile cilia. Exome sequencing is a powerful tool that can help "democratize" the diagnosis of PCD, which is currently limited to highly specialized centers.

Geographic distribution of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Saudi Arabia.

INTRODUCTION: Cystic fibrosis (CF) has been reported before in Saudi Arabia and the Gulf area. It has been found that screening for 10 most common cystic fibrosis transmembrane conductance regulator (CFTR) mutations can detect 80% of positive CFTR cases. OBJECTIVES: To determine the geographic distribution of the most common CFTR variants in 5 regions of Saudi Arabia. METHODOLOGY: A retrospective chart review of all CFTR variants conducted from January 1, 1992 to December 1, 2017. RESULTS: The ten most common CFTR mutations in the Saudi population were as follows: p.Gly473GlufsX54 (17%), p.Phe508del (12%), p.Ile1234Val (12%), 3120+1G > A (11%), 711+1G > T (9%), p.His139Leu (6%), p.Gln637Hisfs (5%), p.Ser549Arg (3%), p.N1303K (3%), and delExon19-21 (2%) along with other variants 79 (20%). In terms of the highest frequency, the c.2988+1G > A (3120+1G > A) variant was found in the eastern province (7.3%) of Saudi Arabia, the c.1418delG (p.Gly473GlufsX54) variant in the northern province (6.8%), the c.579+1G > T (711+1G > T) variant in the southern province (4.8%), the c.3700A > G (p.Ile1234Val) variant in the central province (4.8%), and c.1521_1523delCTT (p.Phe508del) variant in the western province (4.3%). CONCLUSION: The eastern and the northern provinces have the highest prevalence of CF, with the c.2988+1G > A (3120+1G > A) and c.1418delG (p.Gly473GlufsX54) variants showing the highest distribution in the Saudi CF population, which may reflect the effect of consanguinity within the same tribe. Proper family screening and counseling should be emphasized.

Genotype patterns for mutations of the cystic fibrosis transmembrane conductance regulator gene: a retrospective descriptive study from Saudi Arabia.

BACKGROUND: Cystic fibrosis (CF) occurs in populations in Saudi Arabia and the Gulf area. Approximately 2000 known variants have been identified for the CF transmembrane conductance regulator (CTFR) gene. Screening for ten of the most common variants can detect 80% of alleles. OBJECTIVE: Determine the pattern of CFTR variants in the CF population of Saudi Arabia. DESIGN: A retrospective, descriptive. SETTING: Tertiary care center. PATIENTS AND METHODS: We examined the medical records of 396 confirmed CF patients of all age groups that were positive for a CFTR variant from the period of 1 January 1998 to 1 December 2017. MAIN OUTCOME MEASURES: Zygosity, morbidity and mortality patterns of different types of CFTR variants. SAMPLE SIZE: 312 families that included 396 patients. RESULTS: Of 48 variants identified, 6 were novel, having not been described in the medical literature. A homozygous state was found in 283 families (90.7%) and compound heterozygosity in 23 (7.4%). Six families were heterozygous (1.9%). Median age (interquartile range) was 10.2 months (4.4 months to 5.7 years) at diagnosis and 9.7 (5.4-16.5) years at follow up. Of 396 patients, 378 patients (95.5%) survived and 18 (4.5%) died. The ten most common variants identified in descending frequency were: p.Gly473GlufsX54 in 98 alleles (16%), p.Ile1234Val in 66 alleles (11%), F508del in 64 alleles (11%), 711+1G>T in 62 alleles (10%), 3120+1G>A in 62 alleles (11%), p.His139Leuin 38 alleles (6.4%), p.Gln637Hisfs in 30 alleles (5.2%), p.Ser549Arg in 27 alleles (4.5%), p.Asn1303Lys in 14 alleles (2.3%), delExon19-21in 10 alleles (1.6%). This analysis identified 79.2% of our CFTR variants. CONCLUSION: CFTR mutational patterns in our CF population are characterized by a high allelic heterogeneity. The high prevalence of homozygous variants reflects the high level of consanguinity between parents. LIMITATIONS: Our CFTR screening reflected only about 80% of CF patients in Saudi Arabia. CONFLICT OF INTEREST: None.

The prevalence of viral infections in children with cystic fibrosis in a tertiary care center in Saudi Arabia.

INTRODUCTION: Studies have shown that pulmonary exacerbations in cystic fibrosis (CF) patients are associated with respiratory viruses. The most common agent causing viral infections in patients with CF before the age of 3 years is respiratory syncytial virus. OBJECTIVES: To obtain the prevalence of the different types of viral infection in CF patients and to identify its relation with the type of bacterial infection, (CFTR) mutations and pulmonary function test (PFT). METHODOLOGY: A retrospective charts review of 387 patients with CF of all age groups who were screened for the detection of viruses during respiratory exacerbation from the period of January 1, 1984 to June 1, 2016. RESULTS: A total of 159 CF patients had pulmonary exacerbation and had viral PCR obtained. Fifty-eight patients (36%) had positive viral PCR. Males were more commonly infected in 30/58 patients (52%) compared to females in 28 patients (48%). Forty-five of 58 patients (78%) were alive and 13 patients (22%) died. Rhinovirus was the most frequently reported viral PCR in 33/74 sample (45%). Out of 74 viral PCR, 41 (55.4%) were during the colder seasons (October-February) and 33 (44.5%) during the warmer seasons (March-September). During viral infection and viral recurrence, there was an increase in bacterial colonization specifically of H. influenza and staphylococcus aureus. The most common CFTR mutation for the CF viral infection is: 3120+1G>A in Intron 16 in 11/57 patients (19%). The Eastern Province had the highest viral infection of 24 out of 57 patients (42%). Follow-up PFT post viral infection showed no significant difference in the type and the severity of PFT compared to the initial PFT during the viral illness. CONCLUSION: Viral infections contributed to the increase in morbidity and mortality of CF patients in our population, and rhinovirus was the most common causative agent. Viral infections and viral recurrence increased the prevalence of bacterial infection of specific pathogens such as H. influenza and S. aureus. Physicians should be aware to prevent progressive lung damage in CF patients by treating the concomitant viral and bacterial infections. Viral infection may be associated with some common CFTR mutations.