Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes

Background: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. Results: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. Conclusions: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients

Criteria of candidacy for unilateral cochlear implantation in postlingually deafened adults I: Theory and measures of effectiveness

Objectives: The objectives of this study were to distinguish the equivalent-effectiveness, health-economic, and actuarial approaches to specifying criteria of candidacy for medical interventions; to apply the equivalent-effectiveness approach to unilateral cochlear implantation for postlingually deafened adults; and to determine whether the criterion should take age at implantation and duration of profound deafness into account. Design: The study was designed as a prospective cohort study in 13 hospitals with four groups of severely-profoundly hearing-impaired subjects distinguished by their preoperative ability to identify words in sentences when aided acoustically. The groups represent a progressive relaxation of criteria of candidacy: Group I (N = 134) scored 0% correct without lipreading and did not improve their lipreading score significantly when aided; group II (N = 93) scored 0% without lipreading but did improve their lipreading score significantly when aided; group III (N = 53) scored 0% without lipreading when the to-be-implanted ear was aided but between 1% and ~50% when the other ear was aided. Group IV (N = 31) scored between 1% and ~50% without lipreading when the to-be-implanted ear was aided. Measures of speech intelligibility, health utility, and otologically relevant quality of life were obtained before surgery and 9 mo after surgery from each subject. Measures of effectiveness were calculated as the difference between 9-mo and preoperative scores. Results: Effectiveness differed only slightly between groups. Effectiveness was not strongly associated with age at the time of implantation. Greater effectiveness was associated with implantation in the ear with the shorter duration of profound deafness. Cochlear implantation was least effective when the preoperative audiological status of the better-hearing ear was good and the duration of profound deafness of the implanted ear was long. As a result, effectiveness was not significant for the subsets of groups III and IV, who were given implants in ears that had been profoundly deaf for more than 30 yr. Conclusions: The effectiveness of cochlear implantation differs little between groups of candidates who score zero with acoustic hearing aids before surgery and groups who score up to ~50% correct, thereby justifying a relaxation of the criterion of candidacy to embrace some members of the latter groups. The criterion should be based not only on preoperative speech intelligibility but also on duration of profound deafness in the to-be-implanted ear