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Alteration in the ubiquitin-proteasome system results in human disorders with neurological and/or autoinflammatory presentation. Haploinsufficiency of PSMD12, which encodes a subunit of the core component of the proteasome, causes Stankiewicz-Isidor syndrome (STISS), characterized by intellectual disability, autism spectrum disorder, craniofacial dysmorphisms, with or without other congenital anomalies, and autoinflammation. We described six patients (four adults) from two unrelated families carrying a known p.(Arg289*) or a novel p.(Tyr111*) PSMD12 variant. Portraying a completely penetrant condition with inter- and intra-familiar clinical variability, all individuals presented with developmental delay, intellectual disability, craniofacial, and skeletal anomalies. Novel findings in our cohort included unilateral ectopic fingernail, cholesteatoma, oligodontia, and the occurrence of an ovarian teratoma. Most subjects had acne, short stature, and developed obesity since late childhood. Eating behavior was reported. Good sociality and behavioral concern emerged as well. None presented clinical manifestations of autoinflammation and the detected IFN-I signature perturbations were not specific. Together with a complete literature review, we expanded the clinical spectrum of STISS, highlighting the relevance of inherited variants, and discussing challenges in diagnosis and management. We finally consider the intriguing role of PSMD12 in human development and propose to index "onychoheterotopia" among the Human Phenotype Ontology terms., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability., Methods and Results: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10 -8 ). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously ( SPPL2B and RFX6 )., Conclusions: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF., (© 2022 Wiley Periodicals LLC.)