Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review

Abstract

Schuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50–74%), infrequent (26–49%) and rare (less than ≤25%).

A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum

“…The carriers with multi-exon deletion in PACS1 were reported with no medical history of seizures, and the brain MRI scan also demonstrated that the brothers and their father had a normal brain structure ( Figure 3C ). More than 50% of individuals with SHMS have been reported with abnormal height and weight measurements, and 5–10% of these individuals are affected since birth ( Lusk et al, 2020 ; Tenorio-Castano et al, 2021 ). The data on head circumference and height and weight of the two brothers was collected and analyzed.…”

“…The proband The proband's elder brother Frequency (%) Lusk et al, 2020;Seto et al, 2020;Tenorio-Castano et al, 2021 long eyelashes, and a wide mouth. As reported previously, more than 50% of SHMS patients were found to have seizures and structural brain abnormalities (Lusk et al, 2020;Tenorio-Castano et al, 2021).…”

“…The proband The proband's elder brother Frequency (%) Lusk et al, 2020;Seto et al, 2020;Tenorio-Castano et al, 2021 long eyelashes, and a wide mouth. As reported previously, more than 50% of SHMS patients were found to have seizures and structural brain abnormalities (Lusk et al, 2020;Tenorio-Castano et al, 2021). The carriers with multi-exon deletion in PACS1 were reported with no medical history of seizures, and the brain MRI scan also demonstrated that the brothers and their father had a normal brain structure (Figure 3C).…”

“…Most of the reported patients were found to have three distinct types of traits: dysmorphic facial features, developmental delay (DD), and a range of mild-to-severe intellectual disability (ID). Other common clinical features include feeding difficulty, hypotonia, epilepsy, autism, congenital heart diseases, and ocular anomalies ( Lusk et al, 2020 ; Tenorio-Castano et al, 2021 ).…”

“…A heterozygous de novo variation c. 607C > T (p.Arg203Trp) in PACS1 is present in almost all of the reported cases ( Kurt Colak et al, 2020 ; Lusk et al, 2020 ; Seto et al, 2020 ), except another variation c.608G > A (p.Arg203Gln) which affects the same amino acid ( Miyake et al, 2018 ). Since Schuurs-Hoeijmakers first characterized the recurrent de novo variation of PACS1 (c.607C > T) in two unrelated individuals in 2012 ( Schuurs-Hoeijmakers et al, 2012 ), approximately 63 cases with SHMS have been described in the literature until now, including 60 postnatal individuals and three prenatal cases ( Kurt Colak et al, 2020 ; Lusk et al, 2020 ; Seto et al, 2020 ; Gana et al, 2021 ; Tenorio-Castano et al, 2021 ).…”