Craniofacial malformations account for one third of all congenital anomalies. Genetic factors play a vital role, yet the list of causal genes and their mechanisms are far from complete. As part of a larger effort to sequence patients with micrognathia and Pierre-Robin sequence, we identified two candidate pathogenic missense variants in C-terminal binding protein 1 (CTBP1) along with a heterozygous early stop missense variant in alkaline phosphatase (ALPL) in a proband with mandibular hypoplasia. Ctbp1 has been shown to regulate Wnt/β-Catenin signaling but it has not yet been implicated in craniofacial development. Here we generated two orthologous variants of Ctbp1 mimicking the patient variants using genome editing in mice and explored the micrognathia phenotype in combination with a previously reported Alpl null allele. Ctbp1Q148H/G238S; Alplnull/Wt complex heterozygous mutants have smaller mandibles recapitulating the human mandibular hypoplasia. We identified that a reduction in cell proliferation and active β-Catenin levels could possibly account for the micrognathia phenotype in the Ctbp1; Alpl complex heterozygous. These data uncover a novel role for Ctbp1 in craniofacial development and highlight the complex genetic and molecular signaling in the pathogenesis of craniofacial malformations.
P. Iyyanar, Beulah Solivio, K. Weaver et al.· bioRxiv· 0 citations
Pathogenic variants in LZTR1 are an established cause of Noonan syndrome (NS) and uniquely exhibit both autosomal dominant (AD) and autosomal recessive (AR) inheritance. However, the phenotypic spectrum and genotype-phenotype correlations remain incompletely defined. We conducted a multi-center retrospective chart review of patients diagnosed with LZTR1-NS evaluated at three tertiary care centers. Clinical, molecular, and imaging data were systematically collected. A comprehensive literature review (2015-2025) identified 100 additional individuals meeting inclusion criteria. Comparative analyses were performed to evaluate phenotypic patterns by inheritance. Among 21 previously unreported patients aged 6 months to 49 years, 15 had AD NS and 6 had AR NS. Clinical features were largely consistent with prior reports, including high prevalence of craniofacial dysmorphism, neurodevelopmental and multisystem involvement. Cardiac manifestations were frequent, with pulmonary valve stenosis as the most common lesion. Hypertrophic cardiomyopathy appeared more prominent among AR NS. Notably, lymphatic abnormalities were observed at a higher frequency than previously reported. Compared to the literature, our cohort highlights novel findings, including the co-occurrence of AD LZTR1-NS with 22q11.2 deletion and two patients with AR NS with features suggestive of schwannomatosis. These findings expand the clinical spectrum of LZTR1-NS and have important implications for diagnosis, surveillance, and genetic counseling.
H. Jaouadi, Şakir Hicazi, Carolyn R. Raski et al.· American Journal of Medical...· 0 citations
Recent medical advances have significantly improved the life expectancy of individuals with congenital heart disease (CHD); however, these children remain at increased risk of co‐occurring neurodevelopmental disorders (NDD), such as attention‐deficit/hyperactivity disorder and autism spectrum disorder. Although prenatal environmental factors, including placental dysfunction and altered oxygen levels in utero, as well as postnatal events such as cardiac surgery, may contribute to this increased risk, shared genetic factors may also underlie both conditions. Therefore, this study is aimed at investigating genomic, transcriptomic and epigenomic findings in patients with NDD and/or CHD using an integrative multiomic approach. A cohort of 14 trios and one duo was recruited: Two probands had both NDD and CHD, two had CHD only and 11 had NDD only. Blood samples were analysed using whole‐genome sequencing, RNA sequencing and DNA methylation profiling. We identified one large deletion (~2.5 Mb) and seven likely pathogenic/pathogenic (LP/P) variants, including two in autosomal dominant genes relevant to the patients′ phenotypes and five in autosomal recessive genes consistent with carrier status. This included a likely pathogenic de novo splice‐disrupting variant in the chromatin remodelling gene ARID1B, validated by RNA sequencing. DNA methylation analysis revealed epigenetic differences between CHD and NDD patients, with CHD patients showing elevated biological age acceleration. Comparison with a reference cohort of 178 controls identified four probands with extreme methylation dysregulation, including the individual with the ARID1B variant. Overall, these findings highlight the diagnostic and mechanistic value of integrative multiomic profiling in paediatric developmental disease cohorts.
Jamie-Lee M. Thompson, Yun-Kai Gao, Eri Iwasawa et al.· Human Mutation· 0 citations
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