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The PACS2 gene encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation that has been shown to be highly expressed during human prenatal brain development. Pathogenic variants in PACS2 have been recently shown to be implicated in a phenotype with global developmental delay/intellectual disability, seizures, autistic traits, facial dysmorphic features, and cerebellar dysgenesis. Here, we report a 25‐year‐old male with intellectual disability, epileptic encephalopathy, cerebellar dysgenesis, facial dysmorphism, and a previously reported pathogenic variant in PACS2. To our knowledge, this is the oldest patient reported who, in addition to the known phenotype described in PACS2 patients, presented with a vein of Galen malformation and dilated cardiomyopathy as previously unreported findings. [ABSTRACT FROM AUTHOR]

We report a male adult with early infantile‐onset epilepsy, facial dysmorphism, and iridal and choroidal coloboma who had a de novo heterozygous mutation in PACS2, that is, c.625G > A p.(Glu209Lys). This specific mutation was previously reported in a patient with PACS2‐related disorder (early infantile epileptic encephalopathy 66). De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma. According to large‐scale interactome data, WDR37 interacts most strongly, by far, with PACS1 and PACS2. Clinically, coloboma has been described as a feature in a WDR37‐related disorder and a PACS1‐related disorder (Schuurs‐Hoeijmakers syndrome), but not in a PACS2‐related disorder. Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features. The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development. We propose that dysregulation of the WDR37‐PACS1‐PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma. [ABSTRACT FROM AUTHOR]

Whole exome sequencing (WES) has led to the understanding of the molecular events affecting neurodevelopment in an extremely diverse clinical context, including diseases with intellectual disability (ID) associated with variable central nervous system (CNS) malformations, and developmental and epileptic encephalopathies (DEEs). Recently, PACS2 mutations have been causally linked to a DEE with cerebellar dysgenesis and facial dysmorphism. All known patients presented with a recurrent de novo missense mutation, c.625G>A (p.Glu209Lys). Here, we report on a 7‐year‐old boy with DEE, cerebellar dysgenesis, facial dysmorphism and postnatal growth delay, apparently not fitting with any recognized disorder. WES disclosed a de novo novel missense PACS2 variant, c.631G>A (p.Glu211Lys), as the molecular cause of this complex phenotype. We provide a detailed clinical characterization of this patient, and analyse the available clinical data of individuals with PACS2 mutations to delineate more accurately the clinical spectrum associated with this recently described syndrome. Our study expands the clinical and molecular spectrum of PACS2 mutations. Overview of the available clinical data allow to delineate the condition associated with PACS2 mutations as a variable trait, in which the key features are represented by moderate to severe ID, cerebellar dysgenesis and other CNS malformations, reduced growth, and facial dysmorphism. Report on a 7‐year‐old boy with developmental and epileptic encephalopathies, cerebellar dysgenesis, facial dysmorphism and postnatal growth delay with a novel de nova mutation in PACS2. [ABSTRACT FROM AUTHOR]