Genetic variants of small airways and interstitial pulmonary disease in children

Abstract

Genetic variants of small airways and interstitial pulmonary disease have not been comprehensively studied. This cluster of respiratory disorders usually manifests from early infancy (‘lung disease in utero’). In this study, 24 variants linked to these entities are described. The variants involved two genes associated with surfactant metabolism dysfunction (ABCA3 and CSF2RB), two with pulmonary fibrosis (MUC5B and SFTP), one with bronchiectasis (SCNN1B), and one with alpha-1-antitrypsin deficiency (SERPINA1). A nonsense variant, MUC5B:c.16861G > T, p.Glu5621*, was found in homozygous state in two siblings with severe respiratory disease from birth. One of the siblings also had heterozygous SFTPA1:c.675C > G, p.Asn225Lys, which resulted in a more severe respiratory disease. The sibling with only the homozygous MUC5B variant had lung biopsy, which showed alveolar simplification, interstitial fibrosis, intra-alveolar lipid-laden macrophages, and foci of foreign body giant cell reaction in distal airspaces. Two missense variants, MUC5B:c.14936 T > C, p.Ile4979Thr (rs201287218) and MUC5B:c.16738G > A, p.Gly5580Arg (rs776709402), were also found in compound heterozygous state in two siblings with severe respiratory disease from birth. Overall, the results emphasize the need for genetic studies for patients with complex respiratory problems. Identifying pathogenic variants, such as those presented here, assists in effective family counseling aimed at genetic prevention. In addition, results of genetic studies improve the clinical care and provide opportunities for participating in clinical trials, such as those involving molecularly-targeted therapies.

Interstitial lung disease in infancy and early childhood: a clinicopathological primer

“…Molecular pathology has substantially contributed to the evolving classification of chILD; an association of genetic alterations with specific chILD entities has been reported in up to 20% of cases [19][20][21][22]. In a recent analysis of the chILD-EU register, 46% of the cases had genetic testing, with 13% of these allowing a final genetic diagnosis [23].…”

“…Affected children are usually symptomatic immediately after birth or within the first weeks of life. Physiologically, after an early embryonic stage with the formation of outpouchings of the foregut (weeks 4-7), the first 20 generations of airways are formed in the pseudo-glandular stage (weeks 5-17) followed by a canalicular phase (weeks[16][17][18][19][20][21][22][23][24][25][26] with lengthening and…”

A Single-Institution Experience in the Use of Chest Radiographs for Hospitalized Children Labelled as Asthma Exacerbation

“…Respiratory disorders are especially common in our community [10]. In one study, the estimated prevalence of childhood asthma was about 13% [11].…”

A Novel ML Approach for Computing Missing Sift, Provean, and Mutassessor Scores in Tp53 Mutation Pathogenicity Prediction

“…Oliver Poirion et al propose using expressed SNVs (eSNVs) from RNA sequences to locate tp53 variations in tumor subpopulations [15]. Computational procedures have been developed to assess the influence of amino acid substitutions and the frequent occurrence of missense variants in cancer patients [16] [17]. Understanding the effect of missense mutations is crucial for clinical use, especially in distinguishing pathogenic and infectious variants among numerous missense variants.…”