Current practice by clinical diagnostic laboratories is to utilize online prediction programs to help determine the significance of novel variants in a given gene sequence. However, these programs vary widely in their methods and ability to correctly predict the pathogenicity of a given sequence change. The performance of 17 publicly available pathogenicity prediction programs was assayed using a dataset consisting of 122 credibly pathogenic and benign variants in genes associated with the RASopathy family of disorders and limb-girdle muscular dystrophy. Performance metrics were compared between the programs to determine the most accurate program for loss-of-function and gain-of-function mechanisms. No one program correctly predicted the pathogenicity of all variants analyzed. A major hindrance to the analysis was the lack of output from a significant portion of the programs. The best performer was MutPred, which had a weighted accuracy of 82.6% in the full dataset. Surprisingly, combining the results of the top three programs did not increase the ability to predict pathogenicity over the top performer alone. As the increasing number of sequence changes in larger datasets will require interpretation, the current study demonstrates that extreme caution must be taken when reporting pathogenicity based on statistical online protein prediction programs in the absence of functional studies.

In 1979 a "new" syndrome characterized by X-linked inheritance, hypogonadism, gynecomastia, intellectual disability, obesity, and short stature was described. The now-36-year-old propositus was recently referred to the genetics clinic for profound intellectual disability. Fragile X testing initially demonstrated a duplication of the FMR1 region, and upon further testing we identified an Xq27.3-q28 8.05 Mb-long duplication responsible for a syndrome. Our report describes the molecular and clinical aspects of the X-linked syndrome. Our results suggest that male patients with intellectual disability, hypogonadism, short stature, and gynecomastia should be further investigated for rearrangements in the Xq27.3-q28 region. In the future, when more cases of the duplication are identified, it may become possible to more accurately determine the specific genes affected by overexpression and responsible for the phenotype.

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Patient: —Final Diagnosis: Placental mesenchymal dysplasiaSymptoms: Premature rupture of membranesMedication:—Clinical Procedure: AmniocentesisSpecialty: Obstetrics and GynecologyObjective:Congenital defects/diseasesBackground:Placental mesenchymal dysplasia (PMD) is a rare placental lesion that is associated with high perinatal morbidity and mortality. Grossly, PMD is characterized by placentomegaly with thick and tortuous chorionic vessels and abnormal branching over the chorionic plate. Histologically, enlarged edematous stem villi with dysplastic vessels and cistern formation are seen among normal intermediate and terminal villi. PMD has been previously associated with Beckwith-Wiedemann syndrome, paternal uniparental disomy 6, trisomies, Klinefelter syndrome, and androgenetic-biparental whole-gene mosaicism.Case Report:We report a case of PMD in the setting of severe fetal growth restriction (FGR) (birth weight, 380 gm), with delivery at 25 weeks 1-day gestation. There was no maternal history of hypertension. The 25-week and 1-day gestation newborn infant died 20 minutes after delivery. Fetal cells obtained at amniocentesis had a 228kb deletion at 13q12.11 involving the gap junction beta-6 (GJB6) gene detected by single nucleotide polymorphism (SNP) microarray analysis. This finding was not previously reported in the setting of PMD. The histological findings of the placenta also showed some unique features that may have been associated with the specific molecular alteration that included inconspicuous cistern formation, stem villi and cell island complexes, features of shallow implantation, and a uterine pattern of chronic hypoxic placental injury.Conclusions:A case of PMD in a 28-year-old woman with a female infant born at 25 weeks and 1-day gestation was associated with a 13q12.11 deletion in the GJB6 gene and abnormal placental histological features.

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