A rare genetic disorder long considered a disease of boys has now been documented in a young girl carrying a mutation far more severe than any previously reported in a female patient, offering clinicians worldwide a new roadmap for diagnosing a condition that has quietly slipped past pediatricians for years. In a case report and literature review published in Molecular Genetics & Genomic Medicine, a team from Linyi People’s Hospital in China describes a 15-month-old girl with a large deletion sweeping across ten exons of the BRWD3 gene — a defect that wipes out an entire bromodomain, the molecular “reader” the protein uses to interpret chemical tags on DNA-packaging histones. The finding not only expands the known mutation catalog of X-linked intellectual developmental disorder-93, or XLID93, but also spotlights a biological phenomenon that determines how sick girls with the condition actually become: the skewed silencing of one of their two X chromosomes.
The patient first came to medical attention in December 2024, when her parents brought her to the hospital’s child health care department because of delays in gross motor development. Her early history was already complicated: she had been born prematurely at 33 weeks and 6 days of gestation, weighing just 1860 grams, and had spent 21 days in the neonatal unit. By 15 months of age she could lift her head, roll over, sit unsupported, and crawl — milestones she hit roughly on time or only slightly late — but she could not stand or walk independently, and her fine motor skills remained poor. A neurological examination revealed an unusual split: abnormally high muscle tone in her upper limbs and abnormally low tone in her lower limbs, a combination not previously recorded in this syndrome. Her head circumference measured 48.2 centimeters, landing in the 95th to 97th percentile for her age — a hallmark sign of the macrocephaly that defines the disorder in males.
Clinically, the girl also displayed a constellation of subtle facial features that experienced dysmorphologists learn to recognize: slightly widened spacing between the eyes, a low nasal bridge, a prominent forehead, a short neck, and a low posterior hairline. Brain MRI revealed patchy bright signals around the ventricles and mild ventricular widening, while standardized developmental assessments showed scores consistently below normal across gross motor, fine motor, language, and social domains. Karyotyping showed a normal 46,XX complement, and video electroencephalography detected no seizure activity. What set the diagnostic investigation apart, however, was the genetic work: trio whole-exome sequencing performed on the child and both parents uncovered a heterozygous deletion of exons 21 through 30 of BRWD3 — a mutation absent from both parents, confirming it had arisen de novo in the child herself.
The technical machinery behind that discovery is worth unpacking, because it illustrates how rare variant detection has evolved. The researchers employed a copy-number analysis pipeline called ML-ExonCNV, which estimates whether stretches of DNA are missing or duplicated by measuring the depth of sequencing reads across the genome, correcting for GC-content bias, and comparing the results against a library of more than 200 control exomes. Candidate deletions were then screened through an XGBoost machine-learning model before being validated by an orthogonal method — TaqMan probe-based quantitative PCR using the ACTB gene as an internal reference. The qPCR results matched the computational predictions, cementing confidence that exons 21–30 had indeed vanished from one copy of the girl’s BRWD3 gene. The team then turned to protein structure prediction using the AlphaFold database and molecular visualization software, confirming that the deletion completely eliminates one of the protein’s two bromodomains.
That structural loss matters enormously. BRWD3, located on the X chromosome at position Xq21.1, encodes a giant 1,802-amino-acid protein built from eight WD40 repeat domains at one end and two bromodomains at the other. Bromodomains selectively bind acetylated lysine residues on histone tails, making BRWD3 an epigenetic “reader” that helps orchestrate chromatin remodeling, transcriptional regulation, ubiquitination, and signal transduction. Previous female patients with BRWD3 mutations carried point mutations or small frameshifts that typically left at least part of the protein’s functional architecture intact. This girl’s deletion, by contrast, is a sledgehammer: erasing an entire bromodomain is far more likely to cripple the protein’s ability to recognize chromatin marks and regulate gene expression, closer in severity to the null variants seen in affected males.
The gene’s link to brain development runs through an unexpected signaling route. Research in fruit flies has shown that the BRWD3 homolog operates in the JAK/STAT pathway, a versatile communication network governing cell proliferation, hematopoiesis, and the maintenance of neural stem cells in the optic lobe. In mammals, prolonged exposure of neurons to brain-derived neurotrophic factor activates a non-canonical JAK/STAT program whose output includes virtually every major class of ion channel and neurotransmitter receptor in the brain, along with regulators of synaptic plasticity and neurogenesis. Because this same network regulates many genes implicated in epilepsy syndromes, researchers believe its disruption explains why BRWD3 mutation carriers frequently show developmental delay and epilepsy — three of the four previously reported female patients had seizure histories, a warning sign the study’s authors urge clinicians to keep in mind as the current patient ages.
Since the disorder was first linked to BRWD3 in 2007, the vast majority of the roughly 56 reported cases have been male, presenting with universal intellectual disability, language delay, postnatal macrocephaly, frontal bossing, large ears, and often obesity. Only four girls had ever been described, their symptoms generally milder and easily overlooked. The Chinese team’s systematic literature search through April 2026 — spanning PubMed, Web of Science, Embase, Scopus, SpringerLink, and the Cochrane Library — brought the female total to five, including their own patient. Across these five cases, the core phenotypes cluster tellingly: developmental delay appeared in 60 percent, neurological manifestations in 60 percent, head circumference above the 95th percentile in 60 percent, and distinctive facial features in 40 percent, with overall severity milder than in the male population.
The key to that sex difference lies in X-chromosome inactivation, the epigenetic balancing act every female mammal performs early in embryonic development. Because girls carry two X chromosomes and boys only one, female cells randomly silence one copy to equalize gene dosage. The choice is normally a coin flip, but chance, cell competition, and survival advantages can push the ratio off balance — a phenomenon called skewed X-chromosome inactivation, defined as preferential silencing of one parental X in at least 75 percent of cells. Population studies suggest somewhere between 1.5 and 23 percent of healthy women show such skewing, and the degree and direction of the skew can modulate disease severity in X-linked conditions. Roughly 15 to 30 percent of genes on the inactivated X even escape silencing entirely, further complicating the picture.
When the researchers performed X-chromosome inactivation testing on their patient — using methylation-sensitive restriction enzyme digestion combined with capillary electrophoresis — they found the maternally derived X chromosome was inactivated in about 89 percent of her blood cells, meeting the threshold for non-random, skewed inactivation. The trouble is that without phase analysis, the team could not determine whether the mutant or the healthy X carried the deletion, so the causal link between the skew and her symptoms remains a reasoned inference rather than a proven fact. Still, the pattern across the five female cases is striking. All three girls who underwent XCI testing showed skewing, and severity tracked with direction: one patient whose mutant X was preferentially silenced had only mild cognitive difficulties in early childhood, while another whose normal X was silenced 100 percent of the time — leaving the mutant gene fully active — presented with macrocephaly, facial dysmorphism, developmental delay, epilepsy, and additional features including early puberty and ADHD.
The authors are careful about the limits of their conclusions. The girl was born premature, and her brain MRI changes could independently contribute to her motor delays, so the team distinguished features most consistent with XLID93 — the macrocephaly, facial features, and lower limb hypotonia — from those possibly confounded by prematurity. Blood-based XCI testing also cannot capture what is happening in the brain itself, and no in vitro functional experiments were performed to directly test how the deletion destabilizes the BRWD3 protein or disrupts the JAK/STAT pathway. Long-term follow-up will be needed to see whether the child develops the intellectual disability and seizures that characterize the disorder in males.
Even with those caveats, the clinical message is urgent. The researchers recommend early genetic testing for any child presenting with intellectual disability, language delay, macrocephaly, or epilepsy — and for girls specifically, they recommend adding X-chromosome inactivation analysis to the workup. Mild presentations in females are easily missed, they warn, and every missed diagnosis carries a hidden cost: an apparently healthy mother or daughter carrying a silent BRWD3 variant may later give birth to a son with the severe, classic form of the disease. Treating mildly affected girls and women as the hidden link in the transmission chain, the authors argue, is how families can be spared the birth of profoundly affected male children — and how a disorder hiding in plain sight can finally be caught early enough to matter.
Subject of Research: A female patient with X-linked intellectual developmental disorder-93 (XLID93) caused by a novel de novo heterozygous deletion of exons 21–30 in the BRWD3 gene, with analysis of X-chromosome inactivation and genotype-phenotype correlations in reported female cases
Subject of Research: Biology
Article Title: X-Linked Intellectual Developmental Disorder-93 Caused by BRWD3 Mutation in Females: A Case Report and Literature Review
Article References: Xiu, Y., Zhang, Y., Jiao, Y., Wang, W., & Hu, Y. (2026). X‐Linked Intellectual Developmental Disorder‐93 Caused by BRWD3 Mutation in Females: A Case Report and Literature Review. Molecular Genetics & Genomic Medicine, 14(6), Article e70251. https://doi.org/10.1002/mgg3.70251
Image Credits: AI Generated
DOI: 10.1002/mgg3.70251
Keywords: BRWD3, XLID93, X-linked intellectual developmental disorder, X-chromosome inactivation, macrocephaly, bromodomain, developmental delay, whole-exome sequencing, de novo mutation, JAK/STAT pathway, skewed X-inactivation, genetic diagnosis
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Juliet Wilcox. (September 3, 2026). BRWD3 Mutation Identified in Female with X-Linked Intellectual Disability. Scienmag. https://scienmag.com/brwd3-mutation-identified-in-female-with-x-linked-intellectual-disability/
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