Maria Sol Touzon

Alterations in genes involved in glutamatergic neurotransmission are associated with developmental and epileptic encephalopathies (DEE). One of the most extensively studied pathways involves N‐methyl‐D‐aspartate receptors (NMDAR), which play a key role in brain development, synaptic plasticity, learning and memory. We present the case of an 11‐month‐old boy with DEE who began at 2 months of age with afebrile focal‐to‐generalized tonic seizures and focal activity on electroencephalography (EEG). The patient showed developmental delay, resistance to antiseizure medications and frequent, multiple seizure types—including motor focal seizures, epileptic spasms with and without hypsarrhythmia and generalized seizures—together with abnormal movements and EEG findings consistent with epileptic encephalopathy. Whole‐exome sequencing identified a de novo likely pathogenic variant in the GRIN2D gene, affecting one of the transmembrane domains (M3), which is essential for normal NMDAR function and harbours most of the pathogenic variants reported to date. Our case represents the 14th documented case in the literature to date of a patient with GRIN2D ‐related DEE, contributing to the phenotypic characterization of this entity.

Significance: Sex development involves a precise spatiotemporal expression and interactions of numerous genetic factors, including the WT1 (Wilms tumor 1) gene. Complete and partial loss-of-function WT1 variants are associated with 46,XY disorders/differences of sex development (DSD). Some 46,XX individuals develop testis in absence of the testis-determining gene SRY . We describe a genotype/phenotype association where variants impacting the C-terminal zinc finger (ZF4) of WT1 cause testis development in 46,XX individuals. XX mice carrying a pathogenic variant of ZF4 display masculinization of the fetal gonads. Testis formation may be due to inappropriate interaction between the mutated WT1 and an essential ovarian determinant β-CATENIN. These data show that variants affecting a specific domain of a developmental transcription factor can switch organ fate.

The aim of this study was the molecular characterization of the AR gene as the cause of 46,XY disorder in our population. We studied 41, non related, 46,XY disorder of sexual differentiation index cases, having characteristics consistent with androgen insensivity syndrome (AIS). Genomic DNA was isolated from peripheral blood leukocytes of all patients and 25 family members from 17 non-related families. The AR gene analysis revealed an abnormal sequence in 58.5% of the index patients. All of the complete AIS (CAIS) cases were genetically confirmed, while in the partial form (PAIS) a mutation in AR was detected in only 13 (43.3%). Molecular studies revealed other affected or carrier relatives in 87% of the index cases. The AR mutations were found spread along the whole coding sequence, with a higher prevalence in the ligand binding domain. Nine out of 23 (39%) AR mutations were novel. In 17% of patients with detected AR mutations, somatic mosaicism was detected in leucocyte DNA. In our cohort, long-term follow up gender dysphoria, raised as male or female, was not found. Finally, in suspected PAIS, the identification of AR mutation occurred significantly less than in CAIS patients. Improved knowledge of the components of the AR complex and signaling network might contribute to long term outcome and genetic counseling in AIS patients.