RAF2 and TRAF5 are closely related members of the TRAF family of proteins. They are important signal transducers for a wide range of TNF receptor superfamily members, including TNFR1, TNFR2, CD40 and other lymphocyte costimulatory receptors, RANK/TRANCE-R, EDAR, LTbetaR, LMP-1 and IRE1. TRAF2 andTRAF5 therefore regulate diverse physiological roles, ranging from T and B cell signaling and inflammatory responses to organogenesis and cell survival. The major pathways mediated by TRAF2 and TRAF5 are the classical and alternative pathways of NF-kappaB activation, and MAPK and JNK activation. TRAF2 is heavily regulated by ubiquitin signals, and many of the signaling functions of TRAF2 are mediated through its RING domain and likely its own role as an E3 ubiquitin ligase.

Recurrent 2.65 Mb deletions of 8q13.2q13.3 encompassing EYA1 have been recently described in the literature as a cause of branchio-oto-renal syndrome (BOR). Other clinical features of this recurrent microdeletion syndrome are still being delineated. We describe an additional patient with BOR due to microdeletion of 8q13.2q13.3. In addition to BOR related features, our patient presented with distal arthrogryposis that was detected prenatally, a phenotype that has not previously been described in patients with this deletion. © 2016 Wiley Periodicals, Inc.

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a “Dubowitz‐like” condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome‐wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy‐number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next‐generation sequencing. Overall, the DubS‐like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

SCN2A encodes a voltage-gated sodium channel (NaV1.2) expressed throughout the central nervous system in predominantly excitatory neurons. Pathogenic variants in SCN2A are associated with epilepsy and neurodevelopmental disorders. Genotype-phenotype correlations have been described, with loss of function variants typically being associated with neurodevelopmental delay and later onset seizures, while gain of function variants more often result in early infantile-onset epilepsy. However, the true electrophysiological effects of most disease-causing SCN2A variants have yet to be characterized. We report an infant who presented with migrating focal seizures in the neonatal period. She was found to have a mosaic c.2635G>A, p.Gly879Arg variant in SCN2A. Voltage-clamp studies of the variant expressed on adult and neonatal NaV1.2 isoforms demonstrated a mixed gain and loss of function, with predominantly a loss of function effect with reduced cell surface expression and current density. Additional small electrophysiological alterations included a decrease in the voltage-dependence of activation and an increase in the voltage-dependence of inactivation. This finding of a predominantly loss of function effect was unexpected, as the infant's early epilepsy onset would have suggested a predominantly gain of function effect. This case illustrates that our understanding of genotype phenotype correlations is still limited, and highlights the complexity of the underlying electrophysiological effects of SCN2A variants.