A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis

Abstract

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

Expanding the clinical spectrum associated with PACS2 mutations

“…Olson et al suggested that the disease‐causing p.Glu209Lys substitution alters the ability of the autoregulatory domain to modulate the interaction of PACS2 with client proteins participating in processes related to neuronal development and function . Of note, the Glu211 is located within the autoregulatory domain of PACS2 and is close to the residue that was previously reported to be invariantly affected in the disorder . Our finding further confirms the relevance of this region in the control of PACS2 function (Figure ).…”

“…In the majority of these individuals, facial features suggested no specific diagnosis prior to WES. Major craniofacial findings included synophrys, hypertelorism, downslanting palpebral fissures, bulbous nasal tip, wide mouth with downturned corners, and thin upper lip . Similar features also occurred in the present patient, who showed synophrys, highly arched and sparse broad eyebrows, long eyelashes, smooth philtrum, thin everted upper lip vermilion, reminiscent of the Cornelia de Lange facial gestalt.…”

“…Similar features also occurred in the present patient, who showed synophrys, highly arched and sparse broad eyebrows, long eyelashes, smooth philtrum, thin everted upper lip vermilion, reminiscent of the Cornelia de Lange facial gestalt. Of note, while this disorder was not clinically hypothesized by Olsen et al, it was originally suspected in one of the two first patients affected by Schuurs‐Hoeijmakers syndrome, in which WES disclosed a missense mutation in its paralog, PACS1 . This argues for a partial overlap of facial features of PACS ‐related disorders with Cornelia de Lange syndrome.…”

“…PACS2 is a multifunctional protein mainly expressed in the brain, including cerebellum (GTEx, https://gtexportal.org/home/, and FANTOM5, http://fantom.gsc.riken.jp/5/index.html), that acts as a traffic modulator by controlling the endoplasmic reticulum‐mitochondrial communication, with nuclear gene expression . Olson et al suggested that the disease‐causing p.Glu209Lys substitution alters the ability of the autoregulatory domain to modulate the interaction of PACS2 with client proteins participating in processes related to neuronal development and function . Of note, the Glu211 is located within the autoregulatory domain of PACS2 and is close to the residue that was previously reported to be invariantly affected in the disorder .…”

“…Arg203 is highly conserved among orthologs, as well as in the paralog, PACS2 (OMIM 610423). Remarkably, a recurrent de novo heterozygous missense variant in PACS2 was more recently found in 14 unrelated individuals presenting with an NDD partially overlapping with the PACS1 ‐related phenotype . All patients presented with a recurrent missense mutation, c.625G>A (p.Glu209Lys), and had early‐onset epilepsy with focal and generalized seizures, global developmental delay and autistic features, cerebellar dysgenesis and dysmorphic facial appearance.…”