No abstract

Background-Hereditary lymphoedemadistichiasis (LD) is an autosomal dominant disorder that classically presents as lymphoedema of the limbs, with variable age of onset, and extra aberrant growth of eyelashes from the Meibomian gland (distichiasis). Other major reported complications include cardiac defects, cleft palate, and extradural cysts. Photophobia, exotropia, ptosis, congenital ectropion, and congenital cataracts are additional eye findings. Recently, we reported that truncating mutations in the forkhead transcription family member FOXC2 resulted in LD in two families. Methods-The clinical findings in seven additional families with LD, including the original family described by Falls and Kertesz, were determined and mutational analyses were performed. Results-Distichiasis was the most common clinical feature followed by age dependent lymphoedema. There is a wide variation of associated secondary features including tetralogy of Fallot and cleft palate. The mutational analyses identified truncating mutations in all of the families studied (two nonsense, one deletion, three insertion, and one insertion-deletion), which most likely result in haploinsuYciency of FOXC2. Conclusions-FOXC2mutations are highly penetrant with variable expressivity which is not explicable by the pattern of mutations. (J Med Genet 2001;38:761-766)

Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma and other cancers, while germline variants have recently been identified in seven patients with a syndrome associating cardiac, facial and digital anomalies with developmental delay. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants through identification and description of 45 new patients, and to determine the effects of the variants at a molecular level through transcriptomic analysis of patient fibroblasts.Methods We performed exome, targeted capture and Sanger sequencing in a series of patients with undiagnosed developmental disorders. Phenotypic and mutational comparisons Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation We hope you will consider our manuscript for publication in Genetics in Medicine and we look forward to hearing your response.

Exome sequencing is now mainstream in clinical practice. However, identification of pathogenic Mendelian variants remains time-consuming, in part, because the limited accuracy of current computational prediction methods requires manual classification by experts. Here we introduce CAPICE, a new machine-learning-based method for prioritizing pathogenic variants, including SNVs and short InDels. CAPICE outperforms the best general (CADD, GAVIN) and consequence-type-specific (REVEL, ClinPred) computational prediction methods, for both rare and ultra-rare variants. CAPICE is easily added to diagnostic pipelines as pre-computed score file or command-line software, or using online MOLGENIS web service with API. Download CAPICE for free and open-source (LGPLv3) at https://github.com/molgenis/ capice.