Biomedical subjects

Jill Rosenfeld

Publications and source records attributed to Jill Rosenfeld.

3 recordsLinked to original sources

PubMed2026

Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome.

Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male-protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open avenues toward understanding the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

Male↗

PubMed2026

Bipolar disorder-associated variants in RAB5A disrupt its function in endolysosomal trafficking in fruit fly and mammalian systems.

Bipolar disorder is a severe neuropsychiatric disorder associated with significant morbidity and mortality. Although the heritability of bipolar disorder is among the highest of all neuropsychiatric disorders, the specific genetic etiologies for most affected individuals have remained elusive. This is due, in part, to difficulty confirming pathogenicity of genomic variants identified in bipolar disorder populations. From the Bipolar Exomes Browser (BipEX) project, we identified three missense variants in RAB5A in four individuals with bipolar disorder not found in controls. We used a Drosophila overexpression system to evaluate these bipolar disorder-associated variants in RAB5A. We determined that when bipolar disorder-associated RAB5A variants are expressed in fruit flies, synaptic neurotransmission, endolysosomal trafficking, viability, survival and wing morphology are all disrupted. We confirmed that certain bipolar disorder-associated RAB5A variants also disrupt early endosomal trafficking in mammalian cells. This confirms bipolar disorder-associated variants in RAB5A disrupt its normal function. Moreover, Drosophila melanogaster is a viable experimental system to test the pathogenicity of genomic variants associated with psychiatric disorders.

Journal Article↗

PubMed2025

Androgens mediate sexual dimorphism in Pilarowski-Bjornsson Syndrome.

Sex-specific penetrance in autosomal dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1 R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety and hypotonia. Orchiectomy unmasks a growth deficiency phenotype in male Chd1 R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open novel avenues to understand the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

CHD1↗