Meningioma-1 is a transcription activator that regulates mammalian palate development and is required for appropriate osteoblast proliferation, motility, differentiation, and function. Microdeletions involving the MN1 gene have been linked to syndromes including craniofacial anomalies, such as Toriello-Carey syndrome. Recently, truncating variants in the C-terminal portion of the MN1 transcriptional factor have been linked to a characteristic and distinct phenotype presenting with craniofacial anomalies and partial rhombencephalosynapsis, a rare brain malformation characterized by midline fusion of the cerebellar hemispheres with partial or complete loss of the cerebellar vermis. It has been called MN1 C-terminal truncation (MCTT) syndrome or CEBALID (Craniofacial defects, dysmorphic Ears, Brain Abnormalities, Language delay, and Intellectual Disability) and suggested to be caused by dominantly acting truncated protein MN1 instead of haploinsufficiency. As a proto-oncogene, MN1 is also involved in familial meningioma. In this study, we present a novel case of MCTT syndrome in a female patient presenting with craniofacial anomalies and rhombencephalosynapsis, harboring a de novo pathogenic variant in the MN1 gene: c.3686_3698del, p.(Met1229Argfs*87).

To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. Detailed phenotyping and next-generation sequencing (panel and exome). Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

Proximal deletion of 6q is a relatively rare chromosomal abnormality. Reported patients have deletions of different sizes but share partial overlap and present with similar clinical features, and some of them were described prior to the introduction of chromosome microarrays. We describe a male patient with prenatal sonographic findings of nuchal edema, intrauterine growth restriction, renal pelvis dilatation, and oligohydramnios. At birth, facial dysmorphism, retro/micrognathia, a short and wide neck as well as cardiovascular and renal anomalies were noted. His clinical evolution has been marked by failure to thrive, severe developmental delay, and cognitive impairment. The diagnosis of Toriello-Carey syndrome (TCS) was based on his "gestalt." aCGH identified a de novo proximal deletion of 17 Mb in 6q (6q12q14.3). Deletion 6q13q14 seems to be responsible for the main facial features and should be considered within the differential diagnosis of TCS.

Recently, de novo heterozygous variants in DDX3X have been reported in about 1.5% of 2659 females with previously unexplained intellectual disability (ID). We report on the identification of DDX3X variants in two unrelated girls with clinical features of Toriello-Carey Syndrome (T-CS). In patient 1, the recurrent variant c.1703C>T; p.(P568L) was identified when reconsidering X-linked de novo heterozygous variants in exome sequencing data. In patient 2, the DDX3X variant c.1600C>G; p.(R534G) was also detected by exome sequencing. Based on these data, de novo heterozygous DDX3X variants should be considered not only in females with unexplained ID, but also in individuals with a clinical diagnosis of T-CS.

Toriello-Carey syndrome (T-CS), which was first described by Toriello and Carey, is a rare multiple congenital anomaly syndrome characterized by agenesis of the corpus callosum, Pierre Robin sequence, unusual facial appearance, and other anomalies. Tracheal or laryngeal anomalies are reported as a common manifestation of T-CS. These anomalies can lead to respiratory distress and respiratory tract infection. The cause of T-CS is unknown, although there have been reports of patients with a clinical diagnosis of T-CS and a chromosome anomaly. We describe another such patient who was found to have an interstitial deletion of 3q (3q12.1-q21.3). © 2016 Wiley Periodicals, Inc.