Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility.

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.

[Infant gastroesophageal reflux disease: physiological or pathological ?] / Reflux gastrooesophagien du nourrisson : physiologique ou pathologique ?

INFANT GASTRO-ESOPHAGEAL REFLUX DISEASE: PHYSIOLOGICAL OR PATHOLOGICAL ? Gastroesophageal reflux (GER) is defined by the rise of gastric contents into the esophagus, with or without externalization. GER is very common in young infants, with a peak around 4 months, and most often physiological due to high milk intakes and inappropriate relaxation of the lower esophageal sphincter. Evoking a GER disease (GERD) is not always obvious due to signs of poor specificity (crying, irritability, regurgitation). On the other hand, one should not miss warning signs evocative of GERD complicated by esophagitis or of recurrent upper respiratory or ENT infections, or even differential diagnoses (cow milk protein allergy, eosinophilic esophagitis, congenital malformations or brain tumours, etc.). The diagnosis of GERD is clinical but investigations can sometimes be discussed like esophagogastroduodenal endoscopy, 24- hour pH-metry, esophagogastroduodenal follow through. The mechanisms of GERD should be clearly explained to parents and physiological GER should be treated with non-drug measures (adaptation of milk intakes/volumes, thickeners). In the absence of improvement, avoidance of cow's milk proteins for 2 to 4 weeks can be proposed, or even treatment with proton pump inhibitors.

REFLUX GASTRO-OESOPHAGIEN DU NOURRISSON: PHYSIOLOGIQUE OU PATHOLOGIQUE ? Le reflux gastro-oesophagien (RGO) est défini par la remontée du contenu gastrique dans l'oesophage, avec ou sans extériorisation. Le RGO est très fréquent chez le nourrisson, avec un pic vers 4 mois. Il est le plus souvent physiologique, en raison d'une alimentation lactée importante et d'une relaxation inappropriée du sphincter inférieur de l'oesophage. Évoquer un RGO pathologique n'est pas toujours évident, car ses symptômes ont une mauvaise spécificité (pleurs, irritabilité, régurgitations). En revanche, il ne faut pas passer à côté de signes d'alarme évocateurs d'un RGO compliqué par une oesophagite ou par des infections respiratoires hautes ou ORL récidivantes, ni négliger les diagnostics différentiels (allergie aux protéines du lait de vache, oesophagite à éosinophiles, malformations congénitales ou tumeurs cérébrales...). Le diagnostic de RGO est clinique, mais certains examens complémentaires peuvent parfois être discutés : endoscopie oesogastroduodénale, pH-métrie des 24 heures, transit oesogastroduodénal. Il convient de bien expliquer aux parents les mécanismes du RGO et de prendre en charge sa forme physiologique par des mesures non médicamenteuses (adaptation des prises/volumes de lait, épaississants). En l'absence d'amélioration, une éviction des protéines du lait de vache peut être proposée pendant deux à quatre semaines, voire un traitement par inhibiteurs de la pompe à protons.

Optimization of biologics to reduce treatment failure in inflammatory bowel diseases.

Moderate to severe inflammatory bowel disease patients can fail to respond to conventional therapy and/or to biologic treatment. In the era of TNFα antagonists and other non-anti-TNF biologic drugs, it is important to review the literature on biologic treatment failure, which could be defined as primary non-response, secondary loss of response and intolerance. Therapeutic drug monitoring (TDM), that is, drug trough level and antidrug antibodies, should enable to determine the mechanisms of treatment failure and to optimize drug efficacy. There is a consensus on reactive TDM at the time of loss of response. Proactive TDM could be of interest during induction and/or maintenance, but randomized controlled trials are required.

Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses.

BACKGROUND AND OBJECTIVE: Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results. METHODS: WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation. RESULTS: The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials. CONCLUSIONS: This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.