Biomedical subjects

Karin Weiss

Publications and source records attributed to Karin Weiss.

4 recordsLinked to original sources

PubMed2026

A New Case of Lethal Congenital Contracture Syndrome Type 3 With Hyperinsulinism and Optic Atrophy.

Lethal congenital contracture syndrome 3 (LCCS3, MIM #611369) is a rare autosomal recessive neuromuscular disorder caused by biallelic loss-of-function (LOF) variants in PIP5K1C, reported in only two families to date. It typically presents with severe fetal akinesia, arthrogryposis multiplex congenita, and perinatal lethality due to respiratory insufficiency case. Herein, we report a new case with survival beyond birth. Prenatal findings included clubfeet with preserved amniotic fluid volume and fetal movements. The infant was delivered by cesarean section at 37 + 7 weeks following breech presentation and developed respiratory distress requiring 14 days of ventilatory support. Physical examination revealed bilateral talipes equinovarus, flexion contractures of the knees, restricted hip mobility, clenched hands with flexion contractures of the third and fourth fingers, and hyperextension of the second and fifth fingers. Neurologically, he had encephalopathy, profound hypotonia with a frog posture, and abnormal neonatal reflexes with a discontinuous background pattern on cerebral function monitoring. Additional observed features were bilateral optic atrophy and hyperinsulinemic hypoglycemia responsive to Diazoxide. Trio genome sequencing identified a homozygous pathogenic splice-site variant in PIP5K1C (c.1127+1G>A, NM_012398.3). The infant died at 6 months from multisystemic failure. Further studies are warranted to elucidate the pathomechanisms underlying the PIP5K1C defect and its phenotypic consequences.

LCCS3↗

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↗

PubMed2025

A founder variant in TBCB is associated with global developmental delay, autism spectrum, and spastic paraparesis.

PURPOSE: Hereditary spastic paraparesis (HSP) is a genetically diverse group of Mendelian disorders characterized by length-dependent axonal degeneration. Microtubule dysfunction is a known mechanism in HSP that impairs axonal dynamics. TBCB encodes tubulin-folding cofactor B (TBCB), which, along with TBCE, regulates αβ-heterodimer dynamics and neuronal axonal growth. Here, we describe a new form of complicated HSP caused by a founder variant in TBCB. METHODS: Exome sequencing revealed a homozygous c.589T>A p.(Tyr197Asn) variant in TBCB in a cohort of 10 individuals assembled through genematching tools. Protein function was assessed using Saccharomyces cerevisiae ortholog ALF1, and a CRISPR-Cas9-generated homologous mutant in Drosophila melanogaster. TBCB expression and localization were examined in fibroblasts using western blot and immunofluorescence. RESULTS: Participants displayed late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum. TBCB protein levels were reduced in affected fibroblasts. The ALF1 mutant in yeast increased benomyl sensitivity, resembling a loss-of-function phenotype. In Drosophila melanogaster, the homologous mutant led to reduced survival and impaired climbing ability. CONCLUSION: We describe a novel neurodevelopmental disorder with spastic paraparesis and a high carrier rate in the Ashkenazi Jewish population. Our results indicate that TBCB has a vital role in the development of central nervous system and potentially in axonal function in humans.

Humans↗

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↗