Systematic reanalysis of genomic data improves quality of variant interpretation.

As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.

Duplication 3p21----3pter and cyclopia.

We report on a patient with an interchromosomal duplication of 3p, from 3p21 to 3pter, which apparently arose de novo. The infant had multiple malformations including holoprosencephaly and cyclopia. It is possible that duplication 3p has a generalized effect on the holoprosencephalon or the cleavage of the embryonic forebrain. Fibroblasts from the patient are available from the NIGMS Human Genetic Mutant Cell Repository (GM 7216).

Competing signals drive telencephalon diversity.

The telencephalon is the most complex brain region, controlling communication, emotion, movement and memory. Its adult derivatives develop from the dorsal pallium and ventral subpallium. Despite knowledge of genes required in these territories, we do not understand how evolution has shaped telencephalon diversity. Here, using rock- and sand-dwelling cichlid fishes from Lake Malawi, we demonstrate that differences in strength and timing of opposing Hedgehog and Wingless signals establish evolutionary divergence in dorsal-ventral telencephalon patterning. Rock dwellers exhibit early, extensive Hedgehog activity in the ventral forebrain resulting in expression of foxg1 before dorsal Wingless signals, and a larger subpallium. Sand dwellers show rapid deployment of Wingless, later foxg1 expression and a larger pallium. Manipulation of the Hedgehog and Wingless pathways in cichlid and zebrafish embryos is sufficient to mimic differences between rock- versus sand-dweller brains. Our data suggest that competing ventral Hedgehog and dorsal Wingless signals mediate evolutionary diversification of the telencephalon.

The value of serum carcinoembryonic antigen in predicting recurrent disease following curative resection of colorectal cancer.

UNLABELLED: Carcinoembryonic antigen (CEA) estimations are used to facilitate early diagnosis of recurrent disease after treatment for colorectal cancer. PURPOSE: This study was designed to determine the natural history of patients with normal and abnormal levels of CEA. METHODS: Patients undergoing potential curative resection of colorectal tumors (Dukes Stage A-C) entered a prospective, randomized trial comparing two follow-up regimens (to be reported separately) had CEA levels measured every 3 months for two years; then every 6 months for the next three years. In the study protocol, a rise in CEA was not an indication for investigation to determine recurrence unless there was also other evidence of recurrent disease. RESULTS: Three hundred eleven patients were followed for a median of 4.5 (range, 2-5) years. Recurrent disease developed in 98 (32 percent) patients, 57 of whom had an elevated CEA (sensitivity 58 percent), with a median lead time of six (range, 1-30) months from first abnormal CEA to diagnosis of recurrent disease by other means. The specificity, positive predictive value, and negative predictive value of CEA as an indicator of subsequent recurrent disease was 93 percent, 79 percent, and 83 percent, respectively. The sensitivity of CEA for predicting hepatic metastases was 80 percent, with a median lead time of eight (range, 1-30) months, compared with only 46 percent for sites of recurrent disease other than the liver. CONCLUSIONS: CEA was the first indicator of recurrent disease in 58 percent of all patients and in 80 percent of patients with liver metastases. The diagnosis of recurrent disease may be made several months earlier by investigating the first abnormal CEA level, although any benefit in terms of survival remains to be proven.

Prospective study of biofeedback for treatment of constipation.

PURPOSE: This study was designed to evaluate prospectively the results of pelvic floor physiotherapy with the aid of biofeedback in a heterogeneous group of patients with intractable constipation. METHODS: Biofeedback was used to treat 19 patients (age range, 16-78 (median, 63) years) with intractable constipation. Assessment, using visual linear analog scales of symptoms, was performed prospectively by an independent researcher. Biofeedback was performed by a physiotherapist, and patients were required to attend six sessions on an outpatient basis. The cause of constipation was heterogeneous, with no specific disorder being implicated on testing with anal manometry, defecating proctography, and colonic transit time. RESULTS: At six weeks, there was a median 27 percent (range, -8-93 percent) improvement in symptom scores. At six months, there was a median 23 percent (range, -54-64 percent) improvement in symptom scores. These were statistically significant compared with the scores at outset, six weeks (P = 0.0006), and six months (P = 0.012). However, only two (12.5 percent) patients at the six-month follow-up had an improvement of greater than 50 percent in their symptoms. CONCLUSION: Biofeedback is not recommended in the management of constipation.

Prospective trial of pelvic floor retraining in patients with fecal incontinence.

PURPOSE: Our aim was to prospectively evaluate pelvic floor retraining (PFR) in improving symptomatic fecal incontinence. METHODS: PFR was used to treat 30 patients with fecal incontinence (28 women; age range, 29-85 (median, 68) years). PFR was performed by a physiotherapist in the outpatient department according to a strict protocol and included biofeedback using an anal plug electromyometer. Manometry (24 patients), pudendal nerve terminal motor latency (PNTML, 16 patients), and anal ultrasound (14 patients) were done before commencing therapy. Independent assessment of symptoms was done at the commencement of therapy, at 6 weeks, and at 6 and 12 months posttherapy. RESULTS: Twenty patients (67 percent) had improved incontinence scores, with eight patients (27 percent) being completely or nearly free of symptoms. Of 28 patients followed up longer than six months, 14 achieved a 25 percent or greater improvement at six weeks, which was sustained in all cases. Fourteen had an initial improvement of less than 25 percent, with only four (29 percent) showing later improvement (P < 0.0001). There was no relationship between results of the therapy and patient age, initial severity of symptoms, etiology of incontinence, and results of anal manometry, PNTML, and anal ultrasound. CONCLUSIONS: PFR is a physical therapy that should be considered as the initial treatment in patients with fecal incontinence. An improvement can be expected in up to 67 percent of patients. Initial good results can predict overall outcome.