Expanding the clinical spectrum associated with PACS2 mutations

Abstract

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.

Chromosome 14 deletions, rings, and epilepsy genes: A riddle wrapped in a mystery inside an enigma

“…The epileptic encephalopathy of neonatal‐onset, caused by sequence variants of the PACS2 gene, located on chromosome band 14q32.33 4,5 and referred to here as PACS2 syndrome, is worthy of special mention. PACS2 encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation, it is transcribed in brain tissue where it is enriched in glial cell–enriched white matter.…”

“…Finally, the mutation may affect mTORC2/Akt role in neuronal migration and dendritic arborization, 5 and the mTOR complex is causally involved in various forms of genetic and structural epilepsies 34 . Olson et al 5 found the same de novo missense variant p.Glu209Lys in 14 patients, whereas Dentici et al 4 found missense variant p.Glu211Lys in another patient. PACS2 syndrome is a complex condition characterized by hypotonia, motor and intellectual delay, behavioral issues, dysmorphic face with hypertelorism, broad nasal sella and thin upper lip, minor distal limb abnormalities, cerebellar dysgenesis, and very early onset epilepsy.…”

“…As already mentioned, PACS2 sequence variants cause a developmental epileptic encephalopathy characterized by early onset epilepsy, global developmental delay with variable autistic features, facial dysmorphisms, and cerebellar dysgenesis. This phenotype seems to be linked to two similar missense variants, resulting in a reduced ability of the predicted autoregulatory domain to modulate the interaction between PACS2 and its client protein, which may dysregulate several cellular functions 4,5 …”

“…Special attention should also be paid to the potential role of the PACS2 gene, located on chromosome band 14q32.33. Two recent reports show that de novo missense variants of this gene cause neonatal‐onset developmental and epileptic encephalopathy by disrupting the regulatory functions of the gene 4,5 . In this article we review known cases of linear deletion of chromosome 14q and analyze their phenotype, as well as the epilepsy genes contained in each deletion interval, focusing on terminal deletions, overlapping those found in rings.…”

Clinical and genetic characteristics of the early 66th type epileptic encephalopathy (literature review and own observation)

“…К настоящему времени в гене PACS2 описана еще одна нуклеотидная замена c.631G>A (p.Glu211Lys), возникшая de novo у пациента с эпилепсией с дебютом приступов в возрасте 3 дней, дискинезией мозжечка и лицевыми дизморфиями [7]. Первый адверсивный приступ возник на фоне респираторного дистресса и сопровождался потерей сознания.…”