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Biomedical subjects

Sarah Ennis

Publications and source records attributed to Sarah Ennis.

6 recordsLinked to original sources
PubMed2025

Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease.

BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

Humans↗
PubMed2006

Genome scanning by composite likelihood.

Ambitious programs have recently been advocated or launched to create genomewide databases for meta-analysis of association between DNA markers and phenotypes of medical and/or social concern. A necessary but not sufficient condition for success in association mapping is that the data give accurate estimates of both genomic location and its standard error, which are provided for multifactorial phenotypes by composite likelihood. That class includes the Malecot model, which we here apply with an illustrative example. This preliminary analysis leads to five inferences: permutation of cases and controls provides a test of association free of autocorrelation; two hypotheses give similar estimates, but one is consistently more accurate; estimation of the false-discovery rate is extended to causal genes in a small proportion of regions; the minimal data for successful meta-analysis are inferred; and power is robust for all genomic factors except minor-allele frequency. An extension to meta-analysis is proposed. Other approaches to genome scanning and meta-analysis should, if possible, be similarly extended so that their operating characteristics can be compared.

Chromosome Mapping↗
PubMed2006

Fine mapping of the X-linked recessive congenital idiopathic nystagmus locus at Xq24-q26.3.

PURPOSE: To refine the interval for X-linked congenital idiopathic nystagmus at Xq24-q26.3 and to evaluate a novel candidate gene (Muscleblind-like 3 gene [MBNL3]). METHODS: A single pedigree with congenital idiopathic nystagmus (CIN) inherited as an X-linked recessive trait underwent detailed clinical examination including nystagmology and electrophysiological investigation in selected subjects. Following detailed phenotyping, genotyping was performed using 52 microsatellite markers spaced at an average of 5 cM along the X chromosome. Subsequent two-point and multipoint linkage analysis were performed and a candidate gene was screened for mutations by conventional sequencing. RESULTS: Linkage mapping located the disease gene to a 15.5cM interval at Xq24-q26.3, between markers DXS1212 and DXS1062 with a maximum two-point LOD score of 4.24 with both markers DXS8044 and DXS994 (theta=0). Multipoint analysis indicated a LOD score of 4.54 and a critical gene interval of 8.0 cM. No mutations were found in the MBNL3 gene in this pedigree. CONCLUSIONS: We describe a family with an unusual inheritance pattern most consistent with X-linked recessive inheritance with X inactivation causing manifesting females. We refine the linkage interval for X-linked recessive congenital idiopathic nystagmus and exclude MBNL3 as the causative gene in this family.

Chromosome Mapping↗
PubMed2005

Supernumerary marker chromosomes in man: parental origin, mosaicism and maternal age revisited.

The details of all cytogenetic abnormalities diagnosed in the Wessex Regional Genetics Laboratory (WRGL) since 1967 to the present day have been recorded in the Salisbury Treasury of Interesting Chromosomes (STOIC). From this resource, we identified 137 patients with constitutional autosomal supernumerary marker chromosomes (SMC) ascertained in four principal groups: (i) 37% with abnormal phenotypes; (ii) 7% couples with reproductive difficulties; (iii) 47% antenatal diagnoses and (iv) 9% miscellaneous. Overall, 81 (59%) SMCs were mosaics and 56 (41%) nonmosaics. Of the 109 cases with known parental origins, 70% were de novo, 19% maternally and 11% paternally inherited. The chromosomal origins of 112/137 (82%) of the SMCs have been determined by fluorescence in situ hybridization (FISH). In all, 36/112 (32%) were derived from nonacrocentric autosomes, and 76/112 (68%) from the acrocentric autosomes 13/21, 14, 15 and 22. Of these acrocentric SMCs, 39 (51%) were derived from chromosome 15, so that SMC(15) constituted 39/112 (35%) of all SMCs with known chromosomal origins. The frequencies with which mosaicism was observed varied considerably according to the chromosomal origin of the SMCs and accounted for 8/39 (20%) SMC(15), 13/37 (35%) SMCs from other acrocentrics and 25/36 (69%) of nonacrocentric SMCs. The data were analysed for parental age effects, and only de novo SMC(15)s were found to be associated with a significantly increased maternal age.

Chromosome Disorders↗
PubMed2004

A study of reciprocal translocations and inversions detected by light microscopy with special reference to origin, segregation, and recurrent abnormalities.

We analyzed 448 independently ascertained reciprocal translocations and 220 inversions referred to our diagnostic laboratory. Twenty-eight percent of the translocations and 8.5% of the inversions arose de novo, the proportion being influenced by the method of ascertainment. It was highest, 47%, among translocations ascertained through an abnormal phenotype. With the exception of the 3:1 unbalanced segregants, the remainders were equally likely to have been paternally or maternally inherited. The segregation from balanced translocation and inversion carriers showed an equal number of offspring with a normal chromosome constitution and with a balanced rearrangement. The number of unbalanced segregants among the translocations was 2.7% where the proband was balanced, and 19.2% where the proband was unbalanced. There was only a single unbalanced inversion. A search for recurring translocations showed only the well documented t(11;22) to occur with unusual frequency in our series and those of others, and we concluded that the few other translocations that were seen on more than one occasion were likely to be identical by descent (IBD). Similarly the majority of the recurring inversions, with the exception of "common variants," seemed likely to be IBD. However, eight inversions recurred in our data and in most other series and may well be genuine independent rearrangements. A search of the known olfactory receptor (OR) loci and duplicons suggested that such sequences did not form an important contribution to the breakpoints of recurring rearrangements detected by light microscopy.

Chromosome Aberrations↗