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

Abstract

PACS1 neurodevelopmental disorder (PACS1-NDD) is a category of rare disorder characterized by intellectual disability, speech delay, dysmorphic facial features, and developmental delay. Other various physical abnormalities of PACS1-NDD might involve all organs and systems. Notably, there were only two unique missense mutations [c.607C > T (p.Arg203Trp) and c.608G > A (p.Arg203Gln)] in PACS1 that had been identified as pathogenic variants for PACS1-NDD or Schuurs-Hoeijmakers syndrome (SHMS). Previous reports suggested that these common missense variants were likely to act through dominant-negative or gain-of-function effects manner. It is still uncertain whether the intragenic deletion or duplication in PACS1 will be disease-causing. By using whole-exome sequencing, we first identified a novel heterozygous multi-exon deletion covering exons 12–24 in PACS1 (NM_018026) in four individuals (two brothers and their father and grandfather) in a three-generation family. The younger brother was referred to our center prenatally and was evaluated before and after the birth. Unlike SHMS, no typical dysmorphic facial features, intellectual problems, and structural brain anomalies were observed among these four individuals. The brothers showed a mild hypermyotonia of their extremities at the age of 3 months old and recovered over time. Mild speech and cognitive delay were also noticed in the two brothers at the age of 13 and 27 months old, respectively. However, their father and grandfather showed normal language and cognitive competence. This study might supplement the spectrum of PACS1-NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant.

Phosphofurin Acidic Cluster Sorting Protein 1 Syndrome: Insights Gained on the Multisystem Involvement Reviewing Encoded Protein Interactions?

“…However, their father and grandfather showed normal language and cognitive competence suggestive of no effect on loss of function caused by deletion in the PACS1 gene. 9 Almost all cases reported till date after an initial report of SHMS by Schuurs and Hoeijmakers in two unrelated individuals of a de novo variation of PACS1 (c.607C > T) are reported to harbor the same heterozygous variation in PACS1 neurodevelopmental disorder. Only one another variation c.608G > A (p.Arg203Gln) which affects the same amino acid has been reported in addition to this variant.…”

Molecular Basis of the Schuurs–Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches

“…The PACS1 -NDD was first described in two unrelated male patients in 2012 [ 1 ]. Since then, about 100 patients have been reported in the literature [ 1 , 3 , 4 , 5 , 6 ]. All patients are described have a neurodevelopmental delay with an intellectual disability and psychomotor retardation.…”

“…More recently, a multi-exon deletion of PACS1 has been reported [ 6 ]. Liu and Cols found in four members of a three-generation pedigree the deletion of the exons 12 to 24 in the PACS1 gene.…”

“…Liu and Cols found in four members of a three-generation pedigree the deletion of the exons 12 to 24 in the PACS1 gene. However, the phenotype of this variant was milder, with slight speech and cognitive delay, only affecting two members of the last studied generation [ 6 ]. Furthermore, several databases have reported chromosomal reorganizations where the PACS1 gene is involved (ClinVar, DECIPHER) [ 27 , 29 ].…”

“…It was firstly described in 2012 in two patients with intellectual disability (ID) and a striking facial resemblance; they both carried the same mutation in the PACS1 gene [ 1 ]. To date, less than a hundred patients with PACS1 -NDD have been genetically diagnosed, and, surprisingly, only three pathogenic variants have been reported [ 1 , 3 , 4 , 5 , 6 ]. Furthermore, most of the patients have been described in the last few years, when the PACS1 gene was included in the gene panel analysis for neurodevelopmental disorders; therefore, it is possible that the prevalence of this syndrome could be underestimated.…”