Fragile X syndrome, an X-linked dominant disorder with reduced penetrance, is associated with intellectual and emotional disabilities ranging from learning problems to mental retardation, and mood instability to autism. It is most often caused by the transcriptional silencing of the FMR1 gene, due to an expansion of a CGG repeat found in the 5′-untranslated region. The FMR1 gene product, FMRP, is a selective RNA-binding protein that negatively regulates local protein synthesis in neuronal dendrites. In its absence, the transcripts normally regulated by FMRP are over translated. The resulting over abundance of certain proteins results in reduced synaptic strength due to AMPA receptor trafficking abnormalities that lead, at least in part, to the fragile X phenotype.

Without intervention, classic galactosemia is a potentially fatal disorder in infancy. With the benefit of early diagnosis and dietary restriction of galactose, the acute sequelae of classic galactosemia can be prevented or reversed. However, despite early and lifelong dietary treatment, many galactosemic patients go on to experience serious long-term complications including cognitive disability, speech problems, neurological and/or movement disorders and, in girls and women, ovarian dysfunction. Further, there remains uncertainty surrounding what constitutes a ‘best practice’ for treating this disorder. To explore the extent and implications of this uncertainty, we conducted a small but global survey of healthcare providers who follow patients with classic galactosemia, seeking to compare established protocols for diagnosis, intervention, and follow-up, as well as the outcomes and outcome frequencies seen in the patient populations cared for by these providers. We received 13 survey responses representing five continents and 11 countries. Respondents underscored disparities in approaches to diagnosis, management and follow-up care. Notably, we saw no clear relationship between differing approaches to care and long-term outcomes in the populations studied. Negative outcomes occurred in the majority of cases regardless of when treatment was initiated, how tightly galactose intake was restricted, or how closely patients were monitored. We document here what is, to our knowledge, the first global comparison of healthcare approaches to classic galactosemia. These data reinforce the idea that there is currently no one best practice for treating patients with classic galactosemia, and underscore the need for more extensive and statistically powerful comparative studies to reveal potential positive or negative impacts of differing approaches.

Cleft palate is a frequent and recognizable birth defect attributed to a variety of etiologies including genetic abnormalities and environmental exposures. Bone morphogenetic proteins (BMPs) are involved in embryonic signaling important for a number of developmental processes including bone formation and palate morphogenesis. Recently, haploinsufficency of BMP2 was associated with syndromic forms of cleft palate (CP). Here, we report on a multigenerational family with a history of cleft palate as a result of a 2.3 Megabase (Mb) deletion of chromosome 20p12.3, including the BMP2 gene. In addition to a submucous cleft palate, the proband’s clinical phenotype included failure to thrive (FTT), global developmental delays (DD), and dysmorphic features. The affected father exhibited an overt cleft palate, with a facial gestalt and minor dysmorphic features similar to the proband. The father was otherwise healthy with no history of FTT or DD, suggesting high penetrance, yet variable expressivity for haploinsufficiency of BMP2. The findings presented here provide further evidence for the role of BMP2 in syndromic forms of cleft palate.

Our field of human genetics lost one of its most significant contributors on June 6, 2021. Stephen T. Warren had enormous impact through his discoveries, his service to our field, and especially his mentorship to both colleagues and trainees. Steve’s clever use of somatic cell hybrid methods was key for discovering the mutation in fragile X syndrome, providing a mechanistic answer for the long-standing question of genetic anticipation in humans. He established and led the Department of Human Genetics at Emory University, building a vibrant community, training generations of geneticists and setting an example for us all. His involvement with the American Society of Human Genetics (ASHG) was profound; his membership dated to his undergraduate days in the early 1970s and he had high regard for the Society and its efforts. He served as Editor of The American Journal of Human Genetics, which is the Society’s journal, a member of the Board of Directors, and President. Steve’s accomplishments were recognized with the William Allan Award in 1999 (Figure 1). We write in fond remembrance of our dear colleague; he is missed immensely. Hopefully we can convey the depth of his loss to readers of his beloved journal.

Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.