Expanding the ethnic and clinical spectrum of the IDS c.1122C>T mutation: first report from Pakistan.

Hunter syndrome, also known as Mucopolysaccharidosis type II (MPS II), is a rare X-linked lysosomal storage disorder caused by mutations in the IDS, which encodes the iduronate-2-sulfatase enzyme. The main aim of the current genetic study was to investigate a non-consanguineous Pakistani family segregating Hunter's syndrome. Clinical evaluation, biochemical assays, radiological imaging, and genetic sequencing were performed on the affected individuals. The Family was recruited from Khyber Pakhtunkhwa (KP) province of Pakistan and has two affected male individuals. Routine blood investigations showed low blood sugar (1/2), elevated SGPT (1/2), and increased RDW-CV levels (2/2). Both patients (2/2) presented with a severe phenotype, including cognitive impairment (2/2), coarse facial features (2/2), skeletal abnormalities (2/2), growth delay (2/2), hepatomegaly (2/2), hydrocephalus (2/2), macrocephaly (2/2), visual impairment (2/2), and restricted joint mobility (2/2). A previously reported hemizygous c.1122C>T mutation in exon 8 of the IDS. The identified mutation presumably creates an aberrant splicing and leads to the deletion of 20 amino acids in the open reading frame, which would distort the local folding of the polypeptide chain and lead to loss of its interacting sites. MRI analysis demonstrated typical MPS-II-related abnormalities, including enlarged perivascular spaces, ventriculomegaly, posterior fossa and sella turcica deformities, and spinal cord compression due to periodontoid thickening and spinal stenosis. Although the c.1122C>T (IDS) mutation is not novel, its identification in a Pakistani Pashtun family is reported here for the first time, contributing to the ethnic and geographic mapping of MPS II. This study underscores the importance of population-specific mutation data for effective genetic counseling, early diagnosis, and carrier screening.