Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive carbohydrate metabolism disorder caused by mutations in SLC2A2 encoding the glucose transporter 2 (GLUT2) protein. The clinical manifestations include hepatomegaly, conditional hypo/hyperglycemia, rickets, short stature and proximal renal tubular dysfunction. GLUT2 regulates monosaccharide homeostasis through sugar sensing and transmembrane transportation during high/low glucose levels. In the current study, we present two siblings suffering from FBS. The patients presented with doll-like facies, failure to gain weight and height, abdominal distension and firm hepatomegaly. The family had a history of deaths of twin male siblings in the neonatal period and twin female siblings at ages 10 months and 2.5 years, respectively. Clinical presentation and biochemical investigations including a complete blood count, electrolytes, liver and renal function tests suggested FBS. Mutation screening of SLC2A2 confirmed the diagnosis with identification of a novel homozygous splice site variant predicting an in-frame deletion [p.(Gly166-S169del)] in the GLUT2 protein. The in-silico analysis predicted the variant to affect the three-dimensional conformation of the fourth transmembrane helix of the encoded protein, rendering the non-functionality of GLUT2 in both patients of the family under study.

<b><i>Introduction:</i></b> Mucopolysaccharidosis type II (MPS-II) or Hunter syndrome is a rare X-linked recessive disorder caused by genetic lesions in the IDS gene, encoding the iduronate-2-sulfatase (IDS) enzyme, disrupting the metabolism of certain sulfate components of the extracellular matrix. Thus, the undegraded components, also known as glycosaminoglycans, accumulate in multiple tissues resulting in multisystemic abnormalities. <b><i>Objective:</i></b> To uncover causative genetic lesions in probands of three unrelated Pakistani families affected with rare X-linked recessive Hunter syndrome. <b><i>Methods:</i></b> Screening of the IDS gene was performed in six individuals (three patients and their mothers) through whole genomic DNA extraction from peripheral blood followed by PCR and Sanger sequencing. MutationTaster, PROVEAN, Human Splicing Finder, Swiss-Model, and SwissPdbViewer were used for in silico analysis of identified variants. <b><i>Results:</i></b> All probands were presented with coarse facies, recurrent respiratory tract infection, and reduced IDS activity. Molecular screening of IDS identified three different pathogenic variants including a novel duplication variant c.114_117dupCGTT, a novel splice site variant c.1006 + 1G&#x3e;C, and a nonsense variant c.1165C&#x3e;T. In silico analysis unanimously revealed the pathogenic nature of the variants due to their deleterious effects upon the encoded enzyme. <b><i>Conclusion:</i></b> Identified variants predictably lead to either the expression of a nonfunctional enzyme due to partial loss of SD1 and complete loss of SD2 subdomains or a complete lack of the IDS enzyme as a result of nonsense-mediated mRNA decay. Our study provides the first genetic depiction of MPS-II in Pakistan, expands the global IDS mutation spectrum, may provide insights into the three-dimensional structure of IDS, and should benefit the affected families in genetic counseling and prenatal diagnosis.