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Introduction: Pilarowski-Bjrnsson syndrome (PILBOS) is a rare autosomal dominant neurodevelopmental disorder associated with heterozygous variants in the chromatin remodeler CHD1.The initial 2018 description of the syndrome included six affected females, prompting speculation that the condition might be male-lethal.Since then, additional individuals of both sexes have been reported, but no extensive cohort study has systematically evaluated sex distribution, variant spectrum, or phenotype-genotype relationships.We assembled the largest PILBOS cohort to date to clarify the range of pathogenic variation, characterize core clinical features, and assess potential sex-specific effects.Methods: Phenotypic and variant information of individuals with CHD1 variants was collected through GeneMatcher, direct contact with clinicians and families, and an online patient support network.Variant assessment followed ACMG/AMP guidelines when sufficient evidence was available.Missense variants were further evaluated using AlphaMissense to predict possible structural and functional impact.Only variants with substantial supporting evidence (likely pathogenic, pathogenic, or predicted deleterious/uncertain by AlphaMissense) were used to define the core phenotypes.Sex-specific analyses used ztests or Welch's t-tests as appropriate.Results: We identified 48 previously unreported unrelated individuals across 14 countries.Combined with the eight published probands, our cohort included 56 affected individuals (39 males, 17 females) with 52 distinct CHD1 variants.Among these, 29 were missense variants (n=33 individuals), 20 were truncating loss-of-function (LOF) variants (n=20), one was a stop-loss variant, and two involved possible non-canonical splice sites.Three missense variants were recurrent.Using ACMG/AMP criteria, 23 of 52 variants (44%) were classified as likely pathogenic.Most missense variants remained variants of uncertain significance, but AlphaMissense predicted that 16 missense variants in 20 individuals were likely to disrupt protein structure or function.In the missense subset, 12 variants (41%) were predicted deleterious, 4 (14%) uncertain, and 13 (45%) benign.Among the 20 individuals carrying putatively disruptive missense variants, sex distribution was equal (10 males, 10 females).In contrast, LOF variants were enriched in males (z = 2.68, p = 0.007): 16 males (80%) vs four females (20%).After excluding two non-canonical splice-site variants lacking interpretable functional prediction, 36 variants across 40 individuals were used to define the core phenotypes.Individuals with disruptive missense variants most frequently exhibited developmental delay (85%), speech apraxia or speech delay (80%), intellectual disability (67%), and autism spectrum disorder (65%).In the LOF group, speech apraxia or speech delay (95%) and autism spectrum disorder (70%) were most common, followed by developmental delay (60%) and intellectual disability (47%).Phenotypic scoring demonstrated that females with missense variants had significantly higher severity scores than males with missense variants (p = 0.0127, Welch's t-test), whereas no sex difference was observed among individuals with LOF variants.Animal work done by our laboratory shows that some disease phenotypes such as growth retardation and neurobehavioral phenotypes are exclusively seen in female animals carrying a patient specific missense variant (Chd1 R616Q/+ ).Importantly, these sex-dependent disease phenotypes are rescued by androgen supplementation in females and emerge in males upon castration.Population genetic analysis further suggests an overrepresentation of rare missense variants in healthy human males.Conclusion: Our findings suggest that males may be protected from CHD1 effects, suggesting that PILBOS is an autosomal dominant condition with strong sex-determined penetrance.If this phenomenon occurs in other currently unknown disorders, it may be challenging to uncover them without taking sex into account.Future work involves defining a PILBOS-specific methylation episignature to improve the interpretation of missense variants.We additionally plan to assess testosterone levels and further elucidate phenotypes after puberty to understand the role of androgen signaling on the PILBOS phenotype.