Despite increasing knowledge of disease-causing genes in human genetics, approximately half of the individuals affected by neurodevelopmental disorders remain genetically undiagnosed. Part of this missing heritability might be caused by genetic variants outside of protein-coding genes, which are not routinely diagnostically investigated. A recent preprint identified de novo variants in the non-coding spliceosomal snRNA gene RNU4-2 as a cause of a frequent novel syndromic neurodevelopmental disorder. Here we mined 164 whole genome sequencing (WGS) trios from individuals with neurodevelopmental or multiple congenital anomaly disorders that received diagnostic genomic investigations at our clinic. We identify a recurrent de novo RNU4-2 variant (NR_003137.2(RNU4-2):n.64_65insT) in a 5-year-old girl with severe global developmental delay, hypotonia, microcephaly, and seizures that likely explains her phenotype, given that extensive previous genetic investigations failed to identify an alternative cause. We present detailed phenotyping of the individual obtained during a 5-year follow-up. This includes photographs showing recognizable facial features for this novel disorder, which might allow prioritizing other currently unexplained affected individuals sharing similar facial features for targeted investigations of RNU4-2. This case illustrates the power of re-analysis to solve previously unexplained cases even when a diagnostic genome remains negative.

The increasing demand for advanced genomic services has finally come to the attention of healthcare systems and stakeholders who are now eager to find creative solutions to increase the pool of genomic literate providers. Training in genetics and dysmorphology has historically been conducted as a self-driven practice in pattern recognition, ideally within a formal or informal apprenticeship supervised by a master diagnostician. In recent times, case-based learning, framed by flipped classroom pedagogy have become the preferred teaching methods for complex medical topics such as genetics and genomics. To illuminate this perspective, our article was written in honor of the teaching style and pedagogy of Dr John M. Graham Jr and his lifelong commitment to medical education and mentoring.

Pituitary hormone deficiencies may occur in children with midline defects; in these cases, hypogonadism is usually hypogonadotropic. Herein, we report a boy at the age of 13.8 years with mild mental retardation, previously operated for complete cleft palate (isolated) and presented with hypoglycemia due to isolated secondary adrenal insufficiency, who further had a decrease in testicular size with increased follicle-stimulating hormone level (hypergonadotropic hypogonadism) and diagnosed with Klinefelter syndrome. Klinefelter syndrome in childhood is rarely diagnosed and cases are observed in a wide spectrum. Although some regional duplications of the X chromosome also show midline defects such as spina bifida-neural tube defects, mental retardation, hypopituitarism (mostly growth hormone deficiency); coexistence of Klinefelter syndrome and isolated secondary adrenal deficiency/midline defect in our case may also be coincidental. However, to our knowledge, this is the first case in literature with this association in a patient with a 47, XXY karyotype.

Balanced de novo non-robertsonian translocations (non-RTs), which involve acrocentric chromosomes, are rare findings in clinical cytogenetics and may be associated with an abnormal phenotype. These translocations, detected by conventional karyotyping, are found in approximately 1:1,000 neonates. In most of these cases, one of the parents carries the same translocation. In this study, we report a rare non-RT involving chromosomes 15 and 22 defined as 45, XX, -22,der(15;22)t(15;22)/46, XX, der(15)t(15;22),der(22). To our knowledge, this is the first report of a non-RT t(15;22) with these breakpoints.