A homozygous missense variant in the PLCB4 gene causes severe phenotype of auriculocondylar syndrome type 2.

Auriculocondylar syndrome (ARCND) is a rare craniofacial birth defect characterized by malformations in the mandible and external ear (Question Mark Ear). Genetically, three distinct subtypes of ARCND (ARCND1, ARCND2, and ARCND3) have been identified. ARCND2 is linked to pathogenic variants in the PLCB4 gene (phospholipase C ß4). PLCB4 is a key effector of the EDN1-EDNRA pathway involved in craniofacial development via the induction, migration, and maintenance of neural crest cells. ARCND2 is typically inherited in an autosomal dominant pattern, with recessive inheritance pattern being rare. In this study, we report the first homozygous missense variant (NM_000933.4: c.2050G>A: p.(Gly684Arg)) in the PLCB4 gene causing ARCND in a 3-year-old patient with a severe clinical phenotype of the syndrome. The patient presented with typical craniofacial ARCND features, in addition to intestinal transit defect, macropenis, and hearing loss. These findings further delineate the phenotypic spectrum of ARCND associated with autosomal recessive PLCB4 loss of function variants. Notably, our results provide further evidence that these variants can result in a more severe and diverse manifestations of the syndrome. Clinicians should consider the rare features of this condition for better management of patients.

The Diagnosis and Genetic Mechanisms of Prader-Willi Syndrome: Findings From a Moroccan Population Study.

Background Prader-Willi syndrome (PWS) is a complex genetic disorder caused by a deficit in gene expression on the paternal inherited chromosome 15q11.2-q13. It affects various aspects of growth and development, including feeding, cognitive function, and behavior. Early diagnosis and management of PWS can significantly improve outcomes for patients and their families. Methods In this study, we analyzed a group of 29 clinically diagnosed patients suspected of PWS. All patients were referred to the medical genetics and onco-genetics service for genetic consultation and molecular analysis. We used DNA methylation analysis and fluorescence in situ hybridization (FISH) to confirm the diagnosis and identify the underlying genetic mechanisms. Results Our analysis showed that five out of seven patients (71.43%) with a positive methylation-specific PCR (MSP) had chromosomal deletion by FISH and presented major clinical signs summarized by morbid obesity in 65.21% of cases and neonatal hypotonia in 42.85% of cases. This finding indicates that paternal 15q11-q13 deletion is the most common genetic mechanism involved in PWS. Conclusion The results of this study highlight the importance of early diagnosis and molecular analysis in the management of Prader-Willi syndrome. Our findings contribute to a better understanding of the genotype-phenotype correlation in the Moroccan population and provide families with a rigorous molecular diagnosis, relevant genetic counseling, and multidisciplinary support. Further research is needed to explore the underlying mechanisms of PWS and develop effective interventions to improve outcomes for affected individuals.