Mutations in SCARF2 are responsible for Van Den Ende-Gupta syndrome

Abstract

Van Den Ende-Gupta syndrome (VDEGS) is an extremely rare autosomal-recessive disorder characterized by distinctive craniofacial features, which include blepharophimosis, malar and/or maxillary hypoplasia, a narrow and beaked nose, and an everted lower lip. Other features are arachnodactyly, camptodactyly, peculiar skeletal abnormalities, and normal development and intelligence. We present molecular data on four VDEGS patients from three consanguineous Qatari families belonging to the same highly inbred Bedouin tribe. The patients were genotyped with SNP microarrays, and a 2.4 Mb homozygous region was found on chromosome 22q11 in an area overlapping the DiGeorge critical region. This region contained 44 genes, including SCARF2, a gene that is expressed during development in a number of mouse tissues relevant to the symptoms described above. Sanger sequencing identified a missense change, c.773G>A (p.C258Y), in exon 4 in the two closely related patients and a 2 bp deletion in exon 8, c.1328_1329delTG (p.V443DfsX83), in two unrelated individuals. In parallel with the candidate gene approach, complete exome sequencing was used to confirm that SCARF2 was the gene responsible for VDEGS. SCARF2 contains putative epidermal growth factor-like domains in its extracellular domain, along with a number of positively charged residues in its intracellular domain, indicating that it may be involved in intracellular signaling. However, the function of SCARF2 has not been characterized, and this study reports that phenotypic effects can be associated with defects in the scavenger receptor F family of genes.

Figure 1

Pedigrees of Patients Affected with VDEGS (A–C) The consanguinity and relationship for both patients 1 and 2 are shown in (A). The two patients are related. Information for patient 3 is shown in (B) and for patient 4 in (C). Black denotes patients affected with VDEGS.

Figure 2

Homozygosity Mapping Results Location and region delimiting SNPs of the 2.4 Mb homozygous region on chromosome 22q11 shared by the four VDEGS patients (boxed area). Blue denotes individual homozygous regions and haplotype shared by patients 1 and 2, red denotes homozygous region of patient 3, green denotes the homozygous region of patient 4, and yellow denotes the shared haplotype within the homozygous regions of patients 3 and 4. Patients 3 and 4 reflect complex levels of relatedness within the tribal population. Each patient carries a haplotypically distinct homozygous segment resulting from the most recent consanguinity. However, within these large segments, the two patients share a smaller common haplotype, most likely inherited from a more distant common ancestor of the parents.

Figure 3

Sequencing and Exome Capture Results (A) Presence and effect of c.1328_1329delTG mutation. (B) Presence and effect of c.773G>A mutation. (C) Conservation of residues near 773G>A (p.C258Y) mutation. Black denotes residues conserved across all species; gray denotes residues that are different in at least one species. Asterisk (^∗) indicates the residue changed by the mutation. (D) Exome capture and sequencing results in the mother of patient 1. Red “T”s indicate deviation from RefSeq sequence (bottom). Sequencing shows a heterozygous state of the c.773G>A mutation.