Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for ...the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases.
Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines.
We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders.
Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.
Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function ...of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells
. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies
. Previous studies have identified mutations that affect ciliary structure and nucleation in PCD
, but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance.
Congenital lobar overinflation (CLO) is a congenital overinflation of a pulmonary lobe. The treatment choice depends on the severity of its symptoms. Surgical intervention is indicated for patients ...with significant symptomatology, while a conservative approach is used to treat incidental and mildly symptomatic lesions. However, the conservative approach for children with mild symptoms is not very common among pulmonologist. Therefore, we evaluated this approach to treating mildly symptomatic children.
This retrospective study examined mildly symptomatic patients (n = 14) with a radiological diagnosis of CLO between June 2005 and August 2018 who were treated conservatively at KFSHRC in Riyadh. The participants’ ages ranged between two days and four years, with follow-up period ranged from four months to 10 years.
Fourteen patients with CLO—who were 2 days to four years old and comprised 10 boys (71.4%) and four girls (28.6%)—were treated conservatively. All patients were symptomatic upon presentation, and their main clinical findings were tachypnea (85.7%) and dyspnea (78.6%). A single lobe was affected for ten patients (71.4%). Congenital cardiac anomalies founded in six patients (42.9%). Radiological image showed overinflation of all patients’ affected lobes. Significant mediastinal displacement was observed among two patients (14.3%). During their follow-up periods, nine patients (64.3%) became asymptomatic, three (21.4%) showed improvement, and two (14.3%) remained symptomatic and underwent lobectomy.
The good outcomes for mildly symptomatic children with CLO in our series indicate that the conservative approach can be considered to treat these children at any age, along with close follow-up.
•The conservative treatment approaches can be considered for children with mildly symptomatic CLO at any age.•Close follow-up needed for any indication of a possible future lobectomy, according to their clinical situation.•The patients with CLO who present with clinical findings of severe respiratory distress, severe hypoxemia, hypercarbia, a failure to thrive, or a significant mediastinal shift with herniation of the affected lobe across the mediastinum should be operated upon as soon as possible.
Bacterial infections in CF patients are common and start early in life. The prognosis of the disease is substantially dependent on chronic respiratory infection and inflammation. Pseudomonas ...aeruginosa (PA) infection or chronic colonization have been established to cause a chronic decline in pulmonary function (PFT), and/or increase CF mortality.
To obtain the prevalence of all bacterial pathogens in our CF patients and assess their evolution over time.
A retrospective review of 327 patients with confirmed CF of all age groups, who had respiratory culture samples at the first visit and on a regular follow-up between January 1, 1990 and December 2018, was conducted.
A total of 327 patients had a respiratory culture obtained at presentation. Two hundred and sixteen (66%) of 327 patients are alive, while 111 (34%) have died. Respiratory cultures were taken from nasopharyngeal aspiration (NPA) in 199 patients (61%), tracheal aspirate in 9 (3%), bronchoalveolar lavage (BAL)in one (0.29%), and in 124 patients (38%), sputum was induced. The eastern province contributed to the highest number of patients (122, 37.7%). There is a persistent increase in the prevalence of the common bacteria over the follow-up period of 7 years, namely Hemophilus influenzae (H. influenzae), Staphylococcus aureus (S. aureus), and all Pseudomonas (P. aeruginosa) culture types.
Comparing cultures from the first and last follow-up visits, there was an increase in the prevalence of all (P. aeruginosa) cultures from 120 (34%) to 137 (53%), and a decrease in the prevalence of (S. aureus) and (H. influenzae) during the same follow-up period.
There is a progressive increase in the number of patients with the most pathogenic types of bacteria because of the advanced age at presentation. As more adult patients are enrolled, there is a need for improved awareness regarding the early eradication of pathogenic bacteria to prevent progressive pulmonary damage.
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