WDFY3 Haploinsufficiency Is Associated With Autosomal Dominant Neurodevelopmental Disorders and Macrocephaly

WDFY3 (MIM#617485) defects may manifest neurodevelopmental disorders (NDDs) and opposite effects on brain size based on allelic effect. This case highlights a heterozygous WDFY3 nonsense variant linked to mild-to-moderate NDDs, macrocephaly, and unique facial features. Findings emphasize the importance of exome sequencing in NDDs for accurate diagnosis and clinical management. Neurodevelopmental disorders (NDDs) comprise a heterogeneous group of conditions resulting from abnormal brain development, variably manifesting as intellectual disability (ID), behavioral issues, motor and language deficits, and diverse neurological impairments. Recent evidence suggests that disruptions in shared molecular pathways may explain overlapping NDD features [1]. Exome sequencing (ES) has advanced candidate gene discovery, particularly in patients with unique phenotypes lacking a diagnosis. Here, we report a novel loss-of-function WDFY3 (MIM*617485) variant identified in a pediatric patient and her father, presenting with NDDs and distinctive facial features. The patient, a 10-year-old girl, was the only child of nonconsanguineous parents. The father had a history of language delay and ADHD, while the mother was healthy. Furthermore, it was reported that a paternal uncle and his son presented NDDs, and a second paternal uncle reportedly presented isolated macrocephaly. Born at term after an uncomplicated pregnancy, the patient's birth weight was 3300 g (−0.27 SDS), length 54 cm (2.15 SDS), and occipitofrontal circumference (OFC) 35 cm (0.83 SDS). Mild relative macrocephaly (OFC: 43 cm, 1.90 SDS) was noted at 4 months, and brain ultrasound revealed lateral ventricle asymmetry without major structural anomalies (Figure 1a). By 4 years, MRI confirmed these findings (Figure 1b). Early motor milestones were achieved on time, but language delay was notable, with simple sentences at age seven and complex phrases at nine, following speech therapy. The audiometric screening was unremarkable. At three, a neurological evaluation led to a diagnosis of developmental delay and autism spectrum disorder (ASD) according to ADI-R and ADOS-2, mod.1 tests (Mild-to-Moderate evidence). By age nine, physical examination showed her weight at 40.51 kg (1.53 SDS), height 134 cm (−0.10 SDS), and OFC 58 cm (3.61 SDS), with appropriate pubertal development. Distinctive facial features included a flat forehead, broad nasal bridge, bulbous nasal tip, elongated philtrum, thin upper lip, and pointed chin (Figure 1c,d). The father displayed similar features and post-natal macrocephaly (OFC: 60 cm, 1.90 SDS). Karyotyping and chromosomal microarray showed no anomalies, leading to trio-based ES by next-generation sequencing, exclusively identifying a novel heterozygous pathogenic nonsense variant (NM_014991.6.9156G > A; p.Trp3052Ter) of paternal origin in WDFY3. Relatives were not available for genetic or clinical testing. WDFY3 regulates canonical Wnt signaling, crucial for neurodevelopment from early neural patterning to synaptic plasticity. Dysregulation of Wnt signaling is linked to NDDs, and WDFY3 specifically to autism susceptibility [2]. Although the association between WDFY3 haploinsufficiency and macrocephaly remains unclear, Wdfy3 knockout mouse models show early brain overgrowth due to increased neural progenitor proliferation [3]. Our findings support emerging evidence connecting NDDs to WDFY3 haploinsufficiency. Neurological presentation in our patients aligns with prior reports, including mild to moderate developmental delay, behavioral issues, ASD, and macrocephaly [5]. We expand the clinical spectrum of this disorder by identifying unique facial features and a pattern of early post-natal macrocephaly, with no associated megalencephaly, unlike prior cases that lacked detailed OFC progression. These findings suggest possible intrafamilial variability in WDFY3-related NDD phenotypes, with the father displaying a milder form, including language delay and ADHD. Notably, missense WDFY3 variants may function differently, with impaired autophagy of WNT signaling by mutant WDFY3 reducing brain size, yielding a contrasting phenotype in NDDs [4]. Our results underscore the role of monallelic nonsense WDFY3 variants in an autosomal dominant NDD characterized by mild to moderate developmental delay, early post-natal macrocephaly, and additional neurological and clinical features. Recognition of distinctive phenotypic traits, as illustrated in this case study, may enhance diagnostic precision for this emerging disorder, though phenotypic variability should be expected. V.F., C.C., F.S., and G.N. performed genomic investigations. M.B. and M.L.C. performed phenotyping. L.G. conceived and wrote the manuscript with all authors' input. Informed consent was obtained for all diagnostics, and written informed consent was obtained from parents to publish medical data including photographs, in line with the Declaration of Helsinki. Ethical approval was waived following local guidelines for case report studies. No supplementary analysis was performed on the patients. The authors declare no conflcits of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/cge.14665. The data that support the findings of this study are available from the corresponding author upon reasonable request.