SLC26A2-Related Disorders via the SLC26A2 Gene

Pathogenic variants in the SLC26A2 gene are known to cause the following autosomal recessive conditions:

Achondrogenesis type 1B (ACG1B) is characterized by extremely short limbs with short fingers and toes, flat face, short neck, hypoplasia of the thorax, protuberant abdomen, and hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton (Bonafé et al. 2013. PubMed ID: 20301689). Death occurs prenatally or shortly after birth.

Atelosteogenesis type 2 (AO2) is characterized by rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface hypoplasia, depressed nasal bridge, epicanthus, micrognathia). Other typical findings include ulnar deviation of the fingers, gap between the first and second toes, and clubfoot (Bonafé et al. 2014. PubMed ID: 20301493). AO2 is lethal at birth or shortly thereafter because of pulmonary hypoplasia and tracheobronchomalacia.

Diastrophic dysplasia is characterized by limb shortening, normal-sized skull, hitchhiker thumbs, spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and contractures of the large joints with deformities and early-onset osteoarthritis. Other typical findings include ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. On occasion the disease can be lethal at birth, but most affected individuals survive the neonatal period and develop physical limitations with normal intelligence (Bonafé et al. 2013. PubMed ID: 20301524).

Multiple epiphyseal dysplasia (MED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately half of the affected individuals have some abnormal finding at birth such as clubfoot or clinodactyly. Onset of articular pain is variable, but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished. Functional disability is mild (Bonafé et al. 2014. PubMed ID: 20301483).

SLC26A2-related conditions are inherited in an autosomal recessive manner with complete penetrance. SLC26A2 encodes solute carrier family 26 member A2, a sulfate transporter. This transmembrane protein transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impaired proteoglycan deposition, which is necessary for proper enchondral bone formation (Corsi et al. 2001. PubMed ID: 11570921; Forlino et al. 2005. PubMed ID: 15703192).

To date, ~50 pathogenic variants have been documented (missense: ~60%; truncating: 37%, splicing: ~4%). The Finnish founder mutation c.-26+2T>C has been reported in several SLC26A2-related conditions (Zechi-Ceide et al. 2013. PubMed ID: 23840040); this variant has been also observed in a public database with allele frequency up to ~0.7% in European Finnish populations, and up to 0.1% in the general European population (http://gnomad.broadinstitute.org/variant/5-149340544-T-C). The other three common pathogenic variants are: c.532C>T, p.Arg178*; c.835C>T, p.Arg279Trp, and c.1957T>A, p.Cys653Ser (Bonafé et al. 2014. PubMed ID: 20301493). The c.835C>T, p.Arg279Trp has been observed up to ~0.2% in Ashkenazi Jewish populations, and ~0.15% European populations (http://gnomad.broadinstitute.org/variant/5-149359991-C-T). In the compound heterozygous condition, the c.-26+2T>C variant, along with c.835C>T, p.Arg279Trp has also been found in several Swedish patients with autosomal recessive multiple epiphyseal dysplasia (Mäkitie et al. 2015. PubMed ID: 24598000).

This test is predicted to detect causative pathogenic variants in >95% of individuals affected with Atelosteogenesis type 2 (AO2) (Rossi & Superti-Furga. 2001 PubMed ID: 11241838).

This test is predicted to detect causative pathogenic variants in ~70% of individuals with clinical and radiologic features compatible with autosomal recessive multiple epiphyseal dysplasia (MED) (Jackson et al. 2012. PubMed ID: 21922596). The radiologic sign of double-layered patella in lateral knee radiograph is specific for autosomal recessive MED; the c.1957T>A, p.Cys653Ser variant was found in three patients with this sign (Mäkitie et al. 2003. PubMed ID: 12966518).

No disease related large deletions/duplications have been reported in the SLC26A2 gene.

This test provides full coverage of all coding exons of the SLC26A2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

This test also includes coverage of the c.-26+2T>C variant.