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Purpose: Exome sequencing (ES) is increasingly used for the diagnosis of rare genetic disease. However, some pathogenic sequence variants within the exome go undetected due to the technical difficulty of identifying them. Mobile element insertions (MEIs) are a known cause of genetic disease in humans but have been historically difficult to detect via ES and similar targeted sequencing methods., Methods: We developed and applied a novel MEI detection method prospectively to samples received for clinical ES beginning in November 2017. Positive MEI findings were confirmed by an orthogonal method and reported back to the ordering provider. In this study, we examined 89,874 samples from 38,871 cases., Results: Diagnostic MEIs were present in 0.03% (95% binomial test confidence interval: 0.02-0.06%) of all cases and account for 0.15% (95% binomial test confidence interval: 0.08-0.25%) of cases with a molecular diagnosis. One diagnostic MEI was a novel founder event. Most patients with pathogenic MEIs had prior genetic testing, three of whom had previous negative DNA sequencing analysis of the diagnostic gene., Conclusion: MEI detection from ES is a valuable diagnostic tool, reveals molecular findings that may be undetected by other sequencing assays, and increases diagnostic yield by 0.15%.

Myotonic dystrophy, caused by DM1 CTG/CAG repeat expansions, shows varying instability levels between tissues and across ages within patients. We determined DNA replication profiles at the DM1 locus in patient fibroblasts and tissues from DM1 transgenic mice of various ages showing different instability. In patient cells, the repeat is flanked by two replication origins demarcated by CTCF sites, with replication diminished at the expansion. In mice, the expansion replicated from only the downstream origin (CAG as lagging template). In testes from mice of three different ages, replication toward the repeat paused at the earliest age and was relieved at later ages-coinciding with increased instability. Brain, pancreas and thymus replication varied with CpG methylation at DM1 CTCF sites. CTCF sites between progressing forks and repeats reduced replication depending on chromatin. Thus, varying replication progression may affect tissue- and age-specific repeat instability.

Objective: To assess women's knowledge of and views on the evaluation and reporting of ultrasound soft markers., Methods: A prospective survey of 263 women undergoing 18 to 20 week anatomy ultrasound examination at Mount Sinai Hospital, a level 3 perinatal referral centre for a multi-ethnic population of approximately 2.5 million., Results: Prior to reading an information pamphlet provided in the context of this survey, 30% of women (79/263) reported having heard of the term soft marker and 59% of these women (47/79) had discussed soft markers with their caregiver. When asked their preferences about the reporting of ultrasound soft markers, 53% of women said that soft markers should be reported routinely, 20% said they should be reported when the caregiver thinks it necessary, and 23% preferred they be reported only when they have been discussed prior to the ultrasound examination. A minority of respondents (8%) had not participated in prenatal screening for aneuploidy. All of these women preferred that soft markers be reported only after pre-screening discussion., Conclusion: The study demonstrates that most women have little prior knowledge about routine examination for soft markers during the anatomy ultrasound examination and emphasizes the importance of expanding counselling and informed consent to include this aspect of prenatal screening.

The combination of pulmonary agenesis/dysgenesis/hypoplasia, microphthalmia/anophthalmia, and a diaphragmatic defect (agenesis or eventration) is a rare syndrome presumed to have an autosomal recessive mode of inheritance based on a report of affected siblings born to unaffected parents [Seller et al., 1996]. The condition is known as Spear syndrome and Matthew-Wood syndrome, although genetic heterogeneity cannot be ruled out. We report on eight patients with this condition including a living child, three sibs and three isolated cases. Most presented with fetal ultrasound findings of microphthalmia/anophthalmia, and diaphragmatic eventration/hernia and in five, cardiac abnormalities were also found. The earliest detection was at 20 weeks gestation. This is the second report of sibs affected with this condition, which supports an autosomal recessive mode of inheritance. We present the first and only reported living patient with this condition and expand the intrafamilial, interfamilial, and ethnic variability of this condition. We suggest changing the condition's name to PDAC to reflect the most important components of this condition.

Objective: The purpose of this study was to determine the ability of uterine artery Doppler and placental ultrasound to identify adverse clinical outcomes attributable to severe placental dysfunction in women with second-trimester unexplained elevated maternal serum screening of alpha-fetoprotein and human chorionic gonadotropin., Study Design: Fifty singleton pregnancies with elevated alpha-fetoprotein (3.5 multiples of median [range 2.1 to 10.5]) and human chorionic gonadotropin (5.3 multiples of median [range 2.5 to 21.7]) and a normal fetal anatomical ultrasound were prospectively evaluated with placental ultrasound and uterine artery Doppler at referral between 19 and 23 weeks' gestation., Results: Abnormalities in both placental ultrasound and uterine artery Doppler (n = 24) predicted preterm delivery less than 32 weeks from any cause (n = 24) (75% sensitivity, 75% positive predictive value; likelihood ratio positive 3.3 [1.6 to 6.8]), intrauterine fetal death (n = 12) (100% sensitivity, 50% positive predictive value; likelihood ratio positive 3.1 [2.0 to 5.0]), and intrauterine growth restriction with absent/reversed end-diastolic flow (n = 17) (sensitivity 94%, positive predictive value 67%, likelihood ratio positive 3.9 [2.0 to 6.2]) . Ischemic-thrombotic pathology was present in 88% of placentas examined (n = 32)., Conclusion: Uterine artery Doppler and placental morphology identified most pregnancies with combined abnormal maternal serum screening destined to result in extremely premature delivery and/or perinatal death. Abnormal maternal serum screening reports could include a recommendation for placental ultrasound testing when no fetal explanation has been identified.

We report on an Israeli family originating from Iran in which 4 of 7 brothers born from a consanguineous marriage had juvenile Parkinsonism. Linkage analysis of markers covering the autosomal recessive juvenile Parkinsonism (AR-JP, PARK2, Parkin gene, OMIM #602544) gene resulted in a maximal logarithm of odds score of 2.18. A homozygous deletion that expanded from exon 4 to exon 6 was identified in all the patients. Significant clinical heterogeneity was present between siblings., (Copyright 2005 Movement Disorder Society.)

The time of initiation of levodopa therapy in patients with Parkinson's disease (PD) is still debatable, as is the hypothesis of levodopa toxicity Some researchers argue that late initiation of treatment will delay the appearance of response fluctuations. In the present study, 11 patients in whom treatment with low doses of levodopa was delayed for a mean of 7.9 +/- 3.1 years were followed for a mean of 15.7 +/- 3.3 years. Time of onset of response fluctuations and disease severity were compared with those in 17 patients with fluctuating PD who were treated with levodopa from disease onset. There was no significant change in time to onset of response fluctuations and dyskinesias once levodopa treatment was started, and late initiation of levodopa did not affect disease progression. The authors conclude that the decision of when to initiate levodopa treatment should be taken according to the patient's needs.

Chromosome analysis of a locally invasive uveal melanoma revealed monosomy 3 and i(8q). Sublines with multiple copies of the i(8q) were also present. Loss of heterozygosity for genes on chromosome 3 and duplication of genes on 8q may play an important role in progression of uveal melanoma.

A system of emotional control of behavior is believed to be lateralized to the right hemisphere. Given that dopaminergic pathways are involved in affective behavior, depression, which is recognized as an integral part of Parkinson's disease, may be associated with a dopamine imbalance. The present study examined this hypothesis in patients with unilateral symptomatology indicating either left hemisphere parkinsonism (LHP) or right hemisphere parkinsonism (RHP). Sixteen patients were tested on a battery of neuropsychological tests and several scales for evaluating mood. The two groups did not differ significantly on either cognitive or emotional measures. However, RHP patients rated themselves higher on the Present Scale of Cantril, and showed some neglect of the left visual field, as compared to LHP patients.

Ninety-three patients with a diagnosis of Parkinson's disease, otherwise unselected, were specifically evaluated for organic mental syndrome (OMS) and other neurologic motor signs other than those referrable to extrapyramidal dysfunction; in addition, they had cranial computerized tomography (CT) to measure any structural changes in brain parenchyma. Cortical (sulci) atrophy and ventricular enlargement as CT signs of cerebral atrophy were correlated with different clinical patterns of the disease. An age-adjusted control population, with intact mentation, was similarly studied. The presence of classic OMS in a sizable segment of the usual parkinsonian population was invariably associated with CT signs of cerebral atrophy. Atrophic changes on CT scans, however, were not necessarily correlated with any intellectual dysfunction, or only weakly so, independent of age. The "typical" parkinsonian patients without evidence of OMS were indistinguishable from an age-adjusted control group with regard to structural changes in their scans. However, the parkinsonian patients with definite, permanent OMS and other focal neurologic deficit probably constitute a separate or distinct subset of the parkinsonian population, with a pathologic substrate more likely to be similar to that of the so-called Alzheimer-type dementias. Duration of the parkinsonian syndrome was not predictive of either mental status or scan findings, after adjustment for age as a factor.

The frequency of the 'inversion' of flourescent constitutive heterochromatin in chromosome 3 was the same in a sample of 370 retarded persons as in a sample of 222 mentally normal men. It can be concluded that this 'inversion' is not associated with mental retardation. This variant is more common (4%) in the Canadian population we studied than in samples reported by most other authors (0-1.7%). Possibly the founder effect could play a role in the differences. Two cases of homozygotes for this 'inversion' were identified.

The possible phenotypic effect of chromosomal variants is as yet an unsolved problem. QM- and C-banded chromosomes of 100 male patients with idiopathic mental retardation were compared with chromosomes of 100 Royal Military College cadets, as controls. Increased size of 9qh seems to be a factor with possible negative effects. 9qh- was found to be more common in the control sample. Another variant found more often in the retarded subjects was 16qh-. Increased frequencies of Yq+ or small inversions in chromosomes 3 and 9 were not found in the retarded.

The C-bands of two cases of familial, genetically inactive, accessory small chromosomes and five cases of genetically active chromosomes were examined. Inactive chromosomes consist of constitutive heterochromatin and satellites only. In active chromosomes, euchromatin was present. These chromosomes contained two, one or no C-bands, although all these chromosomes were morphologically monocentric. C-banding is more informative than other banding methods for this category of chromosomes.

A series of 203 patients with primary Parkinson's disease treated with L-DOPA, with adequate neurological documentation of mental status at serial intervals during their illness, constitutes the study population. Based on the results of the latest neurological examination, slightly less than one-third (29%) had mental impairment assessed as neurologically significant. Of the eleven clinical variables analysed (Cox regression analysis) for potential influence on the occurrence of an organic mental syndrome, four had a statistically significant effect: (1) the stage of disease at initial neurological examination; (2) the occurrence of acute confusional states; (3) the years of Parkinson's prior to L-DOPA; and (4) the total duration of L-DOPA therapy. The pathogenesis of dementia in this subgroup of Parkinson's disease is discussed.