X-Linked Intellectual Developmental Disorder-93 Caused by BRWD3 Mutation in Females: A Case Report and Literature Review.

objectiveTo report the clinical manifestations and genetic diagnosis of a female patient with X-linked intellectual developmental disorder-93 (XLID93, OMIM#300659) caused by a BRWD3 gene mutation. Systematically summarize the clinical and genetic characteristics of reported female cases and analyze the genotype-phenotype correlation.

methodsA case of XLID93 in a 1-year-and-3-month-old girl was reported. Perform whole-exome sequencing, qPCR copy number verification, X-chromosome inactivation analysis, and three-dimensional protein structure prediction for the child in this case; systematically search relevant databases, and summarize and analyze the phenotypes and genotypes of 5 female patients with BRWD3 mutations reported in the literature to date.

resultsThe patient was a 1-year-and-3-month-old female presenting with delayed gross motor development, unable to stand or walk independently; poor fine motor skills; high muscle tone in the upper limbs and low muscle tone in the lower limbs. Her head circumference was 48.2 cm (95th-97th). She had slightly wide eye spacing, a low nasal bridge, a prominent forehead, a short neck, and a low posterior hairline. There was a heterozygous deletion variation of exon (loss1, EXON 21-30) in the BRWD3 gene of the patient. First-generation verification showed that both parents of the proband were wild-type; this mutation is a de novo mutation, and it is currently impossible to determine whether it is located on the paternal or maternal X chromosome. Protein structure prediction shows that this deletion results in the complete loss of a bromodomain, which may significantly affect the protein function. Through X-chromosome inactivation testing, the inactivation ratio of the maternally derived X-chromosome of the proband was about 89%, indicating non-random inactivation. In summary, the analysis of the clinical and genetic characteristics of five female patients with XLID93 syndrome caused by BRWD3 gene mutations shows that their core clinical phenotypes have obvious commonalities, mainly manifested as: developmental delay (60%), neurological manifestations (60%), head circumference greater than the 95th percentile (60%), and special facial features (40%), with the overall clinical manifestations being milder than those in the male population. Notably, all three female patients who underwent X chromosome inactivation (XCI) testing exhibited skewed XCI, and the severity of the clinical phenotype was closely related to the direction and degree of XCI skewing: patients with preferential inactivation of the mutant X chromosome had milder clinical manifestations (patient 1 had mild cognitive impairment in early childhood); in contrast, patients with preferential inactivation of the normal X chromosome and active expression of the mutant X chromosome had more severe phenotypes (patient 4 had macrocephaly, special facial features, and developmental delay). This further clarifies the important significance of XCI testing in the genotype-phenotype correlation analysis of female patients with MRX93 syndrome.

conclusionClinicians should recommend early genetic testing for children with intellectual disability, language development delay, macrocephaly, or epilepsy. For female patients, X-chromosome inactivation testing should also be completed. Early diagnosis can improve long-term outcomes and prevent the birth of severely affected male children in the same family.