PACS1 syndrome – PACS1 gene

PACS1 syndrome, also known as Schuurs-Hoeijmakers syndrome (SHMS) or autosomal dominant intellectual disability 17 (ID17), is a disorder in which affected individuals have mild to moderate intellectual disability, speech and language difficulties, and a different facial appearance.

Individuals with PACS1 syndrome have distinctive facial features, such as thick and very arched eyebrows, long eyelashes, hypertelorism, descending palpebral fissures, ptosis, rounded nose, wide mouth with commissures down, thin upper lip, and widely spaced and implanted ears low, with fewer folds and grooves than normal. In addition to facial features, affected individuals may have abnormalities in other body systems, such as malformations of the heart, brain, eyes or other organs, including cryptorchidism in men.

Other common signs and symptoms may include difficulty swallowing solid foods and gastroesophageal reflux; features of the autistic spectrum, attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder, self-harm or frustration; seizures; hypotonia; and unsteady gait.

This process is due to mutations in the PACS1 (phosphofurin acidic cluster sorting protein 1) gene, located on the long arm of chromosome 11 (11q13.1-q13.2), which encodes a protein found in the trans-Golgi network, which classifies proteins and other molecules and sends them to their intended destinations inside or outside the cell. PACS1 protein is more active during development before birth.

At least two mutations in the PACS1 gene have been described in individuals with PACS1 syndrome. The most frequent mutation replaces the amino acid arginine with the amino acid tryptophan at position 203 of the protein (Arg203Trp or R203W). It is believed that mutations of the PACS1 gene impair the ability of the protein to participate in the transport of molecules and proteins, which probably results in the accumulation or deficit of these substances inside the cells. In addition, the accumulated molecules and proteins may interfere with the function of the encoded protein from the normal copy of the PACS1 gene, intensifying the disruption in the transport of these substances. It is believed that the altered PACS1 protein impairs the normal development of facial structures, leading to a different facial appearance.

PACS1 syndrome is inherited with an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the process. However, most cases are due to new mutations in the gene that occur during the formation of reproductive cells in the parent or at the beginning of embryonic development. These cases occur in people without history of the disease in their family.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with the PACS1 syndrome, by means of the complete PCR amplification of the exons of the PCAS1 gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).