Characteristic craniofacial defects associated with a novel USP9X truncation mutation.

Germline loss-of-function mutations in USP9X have been reported to cause a wide spectrum of congenital anomalies. Here, we report a Japanese girl with a novel heterozygous nonsense mutation in USP9X who exhibited intellectual disability with characteristic craniofacial abnormalities, including hypotelorism, brachycephaly, hypodontia, micrognathia, severe dental crowding, and an isolated submucous cleft palate. Our findings provide further evidence that disruptions in USP9X contribute to a broad range of congenital craniofacial abnormalities.

Novel TRPS1 frameshift variant in tricho-rhino-phalangeal syndrome type I accompanied by zinc deficiency.

Tricho-rhino-phalangeal syndrome type I (TRPS1), caused by pathogenic variants in the transcriptional repressor GATA-binding 1 gene (TRPS1), is characterized by ectodermal and skeletal anomalies including short stature and sparse scalp hair during infancy. TRPS1 encodes a zinc finger protein transcription factor that contributes to bone homeostasis by regulating perichondral mineralization, chondrocyte proliferation, and apoptosis. Here, a male infant aged 14 months presented with sparse scalp hair, deformed nails, fused teeth, and postnatal growth retardation without neurodevelopmental disorder. As endocrinological measurements revealed low serum zinc levels, he was treated with zinc acetate hydrate, which improved his growth velocity and scalp hair. Whole-exome sequencing revealed that this patient harbored a novel pathogenic de novo heterozygous TRPS1 frameshift variant, c.2819_2822del, p.(His940Argfs*6). Zinc deficiency induces zinc finger protein dysfunction via effects on protein folding and assembly, affecting target gene transcription and apoptosis. The symptoms of TRPS1 are similar to those caused by inadequate levels of zinc, an essential trace element with important roles in tissue growth and repair. Accompanying zinc deficiency may have affected the function of important zinc finger proteins, resulting in phenotypic deterioration. Analysis of zinc metabolism in patients harboring TRPS1 variants will enhance understanding the variety of phenotypes of TRPS1.

Craniofacial and dental characteristics of three Japanese individuals with genetically diagnosed SATB2-associated syndrome.

Craniofacial defects are one of the most frequent phenotypes in syndromic diseases. More than 30% of syndromic diseases are associated with craniofacial defects, which are important for the precise diagnosis of systemic diseases. Special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome (SAS) is a rare syndromic disease associated with a wide variety of phenotypes, including intellectual disability and craniofacial defects. Among them, dental anomalies are the most frequently observed phenotype and thus becomes an important diagnostic criterion for SAS. In this report, we demonstrate three Japanese cases of genetically diagnosed SAS with detailed craniofacial phenotypes. The cases showed multiple dental problems, which have been previously reported to be linked to SAS, including abnormal crown morphologies and pulp stones. One case showed a characteristic enamel pearl at the root furcation. These phenotypes add new insights for differentiating SAS from other disorders.

Compound heterozygous variants of the NARS2 gene in siblings with developmental delay, epilepsy, and neonatal diabetes syndrome.

Neonatal diabetes mellitus (NDM) with developmental delay and epilepsy is classified as developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. The majority of DEND syndrome are due to severely damaging variants of K-ATP channels, and few mitochondria-related genes have been reported. We report here two Japanese siblings who were clinically diagnosed with DEND syndrome in whom NARS2 compound heterozygous variants were detected. Patient 1 was a 3-year-old girl and presented with diabetes ketoacidosis at 3 months old. Patient 2 was a 1-year-old boy who presented with severe hyperglycemia and started insulin therapy at 3 days old. After the first episodes, they both presented with severe developmental delay, hearing loss and treatment-resistant epilepsy accompanied by progressive brain atrophy. Whole-exome sequencing revealed compound heterozygous NARS2 p.R159C and p.L217V variants, and the GATA4 p.P407Q variant in both patients. They were treated by mitochondrial supportive therapy of vitamin B1, L-carnitine, and coenzyme Q10. Patient 2 was withdrawn from insulin therapy at 6 months old. This is the first report of NDM in which variants of the NARS2 gene coding mitochondrial protein were detected. Genetic analysis including mitochondrial genes should be considered in patients with neonatal onset diabetes associated with neurogenic symptoms.