Clinical genetics
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Pain severity ratings and the analgesic dosing requirements of patients with apparently similar pain conditions may differ considerably between individuals. Contributing factors include those of genetic and environmental origin with epigenetic mechanisms that enable dynamic gene-environment interaction, more recently implicated in pain modulation. Insight into genetic factors underpinning inter-patient variability in pain sensitivity has come from rodent heritability studies as well as familial aggregation and twin studies in humans. ⋯ A large number of genetic association studies conducted in patients with a variety of clinical pain types or in humans exposed to experimentally induced pain stimuli in the laboratory setting, have examined the impact of single-nucleotide polymorphisms in various target genes on pain sensitivity and/or analgesic dosing requirements. However, the findings of such studies have generally failed to replicate or have been only partially replicated by independent investigators. Deficiencies in study conduct including use of small sample size, inappropriate statistical methods and inadequate attention to the possibility that between-study differences in environmental factors may alter pain phenotypes through epigenetic mechanisms, have been identified as being significant.
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Twin studies provide a method for estimating the heritability of phenotypes and for examining genetic and environmental relationships between phenotypes. We conducted a systematic review of twin studies of pain, including both clinical and experimental pain phenotypes. Fifty-six papers were included, whereof 52 addressed clinical phenotypes. ⋯ Whereas there is evidence for substantial common genetic risk across many clinical pain conditions, different experimental pain phenotypes appear to be associated with different genetic factors. Recommendations for future research include inclusion of pain intensity scaling and number of pain sites in phenotyping. Furthermore, studies examining the genetic relationships between pain phenotypes, in particular between clinical and experimental phenotypes, should be prioritized.
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Newborn screening (NBS) identifies the majority of classical [salt-wasting (SW) and simple-virilizing (SV)] cases of congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase (21α-OHase) during the first days of life. Diagnosis of classical CAH is confirmed by follow-up serum 17-hydroxyprogesterone and/or the adrenocorticotropin stimulation test; however, neither test definitively distinguishes between the classical subtypes. After confirmation, all newborns are started on hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) treatment. ⋯ Molecular testing on 39 patients (25 identified by NBS) with an already established diagnosis of CAH identified 11 SW patients (8 identified by NBS) whose mutations suggested further biochemical and clinical reassessment of their subtype. Overall, SW accounted for 57.6% of our classical CAH patients, below the generally accepted figure that >75% of classical CAH are comprised of the SW form. In the era of NBS, molecular testing is a valuable supplemental tool identifying patients who may benefit from reassessment of their salt-retaining ability.
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Cancer initiation and progression is controlled by both genetic and epigenetic events. The complexity of carcinogenesis cannot be accounted for by genetic alterations alone but also involves epigenetic changes. Epigenetics refers to the study of mechanisms that alter gene expression without altering the primary DNA sequence. ⋯ Aberrant epigenetic modifications probably occur at a very early stage in neoplastic development, and they are widely described as essential players in cancer progression. Recent advances in epigenetics offer a better understanding of the underlying mechanism(s) of carcinogenesis and provide insight into the discovery of putative cancer biomarkers for early detection, disease monitoring, prognosis, and risk assessment. In this review, we summarize the current literature on epigenetic changes causing genetic alterations that are thought to contribute to cancer, and discuss the potential impact of epigenetics future research.
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Case Reports
A recurrent 1.71 Mb genomic imbalance at 2q13 increases the risk of developmental delay and dysmorphism.
Whole genome profiling such as array comparative genomic hybridization has identified novel genomic imbalances. Many of these genomic imbalances have since been shown to associate with developmental delay, intellectual disability and congenital malformation. Here we identified five unrelated individuals who have a recurrent 1.71 Mb deletion/duplication at 2q13 (Human Genome Build 19: 111,392,197-113,102,594). ⋯ Taken together, 93% and 63% of individuals with this genomic imbalance displayed impaired developmental skills and/or abnormal facial features respectively. This copy number variant (CNV) has not been reported in normal control databases. We, therefore, propose that CNV in this region is a risk factor for developmental delay and dysmorphism.