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Multiple Epiphyseal Dysplasia, Recessive

Synonyms: EDM4, rMED

, MD, PhD, , PhD, , MD, and , MD.

Author Information

Initial Posting: ; Last Update: January 23, 2014.

Estimated reading time: 19 minutes


Clinical characteristics.

Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, e.g., clubfoot, clinodactyly, or (rarely) cystic ear swelling. 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 and ranges from 150 to 180 cm. Functional disability is mild.


Diagnosis of EDM4/rMED is based on clinical and radiographic findings. SLC26A2 is the only gene in which pathogenic variants are known to cause EDM4/rMED.


Treatment of manifestations: Physiotherapy for muscular strengthening and maintaining mobility; cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs (NSAIDs); orthopedic surgery (joint replacement) as indicated; career counseling.

Prevention of secondary complications: Intensive physiotherapy may help in delaying joint contractures and in maintaining mobility.

Surveillance: Radiographs as indicated.

Agents/circumstances to avoid: Sports involving joint overload.

Genetic counseling.

EDM4/rMED is inherited in an autosomal recessive manner. At conception, each sib of a proband with EDM4/rMED has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk is possible if both pathogenic alleles in the family are known and the carrier status of the parents has been confirmed. Requests for prenatal or preimplantation genetic testing for mild conditions such as EDM4/rMED are not common.


Clinical Diagnosis

The diagnosis of recessive multiple epiphyseal dysplasia (EDM4/rMED) is usually established during childhood or early adulthood. The diagnosis is suspected in individuals with the following:

Clinical features

  • Joint pain (usually in the hips and knees). Onset of pain is variable, but usually occurs in late childhood. Some individuals have no pain.
  • Deformity of hands, feet, and knees
  • Scoliosis

Radiographic findings. Skeletal radiographs establish the diagnosis in clinically suspected individuals (see Figure 1). Typical findings include the following:

Figure 1.

Figure 1.

Double patella Ballhausen et al [2003]; reprinted with permission from the BMJ Publishing Group

  • Flat epiphyses with early arthritis (degenerative and painful changes in the articular cartilage of the hip joint)
  • Mild brachydactyly
  • Double-layered patella (i.e., presence of a separate anterior and posterior ossification layer) observed in approximately 60% of individuals on lateral knee radiographs. This finding appears to be age-related and may disappear in adults (Figure 1).

Molecular Genetic Testing

Gene. SLC26A2 (DTDST) is the only gene in which pathogenic variants are known to cause with EDM4/rMED.

Table 1.

Molecular Genetic Testing Used in Multiple Epiphyseal Dysplasia, Recessive

Gene 1MethodVariants Detected 2Variant Detection Frequency by Method 3
SLC26A2 Targeted analysis for pathogenic variantsPanel of selected pathogenic variants 4See footnote 5
Sequence analysis 6Sequence variants>90% 7
Deletion/duplication analysis 8(Multi)exon and whole-gene deletions/duplicationsUnknown; none reported

See Molecular Genetics for information on allelic variants.


% of disease alleles detected in individuals with typical clinical, radiologic, and histologic features of ACG1B


Variant panel may vary by laboratory.


Dependent on variant panel and population tested. The four most common SLC26A2 pathogenic variants (p.Arg279Trp, c.-26+2T>C, p.Arg178Ter, and p.Cys653Ser) account for approximately 70% of disease alleles in all SLC26A2-related dysplasias, but only 10% of disease alleles in ACG1B.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.For issues to consider in interpretation of sequence analysis results, click here.


90% of alleles in individuals with radiologic and histologic features compatible with the diagnosis of sulfate transporter-related dysplasias [Rossi & Superti-Furga 2001].


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband. Clinical and radiologic features may strongly suggest the diagnosis of EDM4/rMED in a proband.

The presence of a double-layered patella at lateral x-ray of the knee is a very specific, although not highly sensitive, sign of EDM4/rMED [Mäkitie et al 2003].

Targeted analysis for the four most common SLC26A2 pathogenic variants is indicated in probands with clinical and radiologic features very suggestive for EDM4/rMED and/or with a clinical diagnosis of MED and no evidence of autosomal dominant inheritance. This test allows identification of at least one pathogenic allele in nearly 100% of EDM4/rMED cases (80% of individuals with EDM4/rMED carry two of the most common pathogenic variants, and another 16% of cases carry one of the most common pathogenic variants in compound heterozygosity with another pathogenic allele).

Sequence analysis of SLC26A2 is indicated in probands with only one heterozygous SLC26A2 pathogenic variant and in probands who tested negative with targeted analysis for pathogenic variants and have very specific signs of EDM4/rMED (double-layered patella and/or classic signs of sulfate transporter-related dysplasia, like clubfoot, cleft palate, and cystic swelling of the ears).

Sequence analysis of SLC26A2 may be considered in simplex cases (i.e., a single occurrence in a family) with no specific signs for a distinct autosomal dominant MED type before testing other known MED-related genes, as recessive pathogenic variants in SLC26A2 are found more frequently in simplex cases than dominant pathogenic variants in other MED-related genes [Jakkula et al 2005].

Single-gene testing. One strategy for molecular diagnosis of a proband suspected of having EDM4/rMED is sequence analysis of only SLC26A2.

Multigene panel. Another strategy for molecular diagnosis of a proband suspected of having EDM4/rMED is use of a multigene panel (see Differential Diagnosis). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Characteristics

Clinical Description

In retrospect, approximately 50% of individuals with recessive multiple epiphyseal dysplasia (EDM4/rMED) have an abnormal finding at birth, such as clubfoot (frequently), clinodactyly, or cleft palate. However, only half of those with findings at birth are suspected of having a skeletal dysplasia.

The majority of affected individuals are diagnosed with a skeletal disorder in childhood, but some are not diagnosed until adulthood. Reasons for seeking medical assistance are mainly chronic joint pain (hips, knees, wrists, and fingers), waddling gait, hand/foot deformities (mild brachydactyly, clinodactyly, clubfoot, broadening of the space between the first and second toes), and mild scoliosis.

There is no specific timing of joint involvement or specific location of joint pain at different ages. Adolescents are usually symptomatic in multiple joints and joint pain increases after physical exercise. Brachydactyly is evident after puberty in most cases.

Habitus is unremarkable in most affected individuals, except for genu valgum in some.

Facies and body proportions are usually normal. Bowing of the extremities is not observed.

Functional disability is mild or absent [Ballhausen et al 2003] in childhood and adolescence; joint involvement progresses slightly in young adults, but hip and knee surgery is usually not needed.

Stature is usually within the normal range prior to puberty and downward crossing of the growth curve does not occur. In adulthood, stature is only slightly diminished, with the median height shifting from the 50th to the tenth centile; range of adult height is 150-180 cm. Approximately one third of affected adults have stature below 2 SD for age.

Genotype-Phenotype Correlations

Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in a spectrum that goes from lethal achondrogenesis 1B (ACG1B) to mild EDM4/rMED.

  • Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural pathogenic variants in transmembrane domains of the sulfate transporter are associated with ACG1B.
  • Pathogenic variants located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene result in less severe phenotypes [Superti-Furga et al 1996a, Karniski 2001, Rossi & Superti-Furga 2001, Karniski 2004].

Variant p.Arg279Trp, the most common SLC26A2 pathogenic variant outside Finland (45% of alleles) is a mild pathogenic variant resulting in the EDM4/rMED phenotype when homozygous and mostly in the diastrophic dysplasia (DTD) phenotype when compounded.

Variant p.Arg178Ter is the second-most common pathogenic variant (9% of alleles) and is associated with a more severe DTD phenotype or even the perinatal-lethal AO2 phenotype, particularly when combined in trans with the p.Arg279Trp pathogenic variant. It has also been found in some cases of more severe rMED and of ACG1B, making it one of two pathogenic variants identified in all four SLC26A2-related dysplasias.

Variants p.Cys653Ser and c.-26+2T>C are the third most common pathogenic variants (8% of alleles for each).

c.-26+2T>C is sometimes referred to as the "Finnish" pathogenic variant because it is much more frequent in Finland than in the remainder of the world population. It produces low levels of correctly spliced mRNA and results in DTD when homozygous and in rMED when compounded with another mild pathogenic variant (p.Arg279Trp, p.Cys653Ser).

Together with p.Arg178Ter, c.-26+2T>C is the only pathogenic variant that has been identified in all four SLC26A2-related dysplasias, in compound heterozygosity with mild (rMED and DTD) or severe (AO2 and ACG1B) alleles [Dwyer et al 2010; Bonafé, unpublished results].

Pathogenic variant p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when compounded with other pathogenic variants.

The same pathogenic variants associated in some individuals with the ACG1B phenotype can be found in individuals with a milder phenotype (AO2 and DTD) if the second allele is a relatively mild pathogenic variant. Indeed, missense variants located outside the transmembrane domain of the sulfate transporter are often associated with a residual activity that can "rescue" the effect of the null allele [Rossi & Superti-Furga 2001].


Multiple epiphyseal dysplasia is a disorder with clinical and genetic heterogeneity. In the past, the disorder was clinically subdivided into the milder Ribbing type, with flattened epiphysis and normal or near-normal stature; the more severe Fairbank type, with round, small epiphyses and short stature; and the unclassified types [International Working Group on Constitutional Diseases of Bone 1998].

The genetic dissection of this heterogeneous group of conditions in recent years has provided a molecular-pathogenic classification of the different subtypes according to the gene involved:

  • EDM4/rMED is classified in the "sulfation disorders group" in the revised Nosology and Classification of Genetic Skeletal Disorders of Bone [Warman et al 2011]. It accounts for about 25% of cases of MED.
  • The other autosomal dominant subtypes of MED are classified in the "multiple epiphyseal dysplasia and pseudoachondroplasia group" in the revised Nosology. The most frequent form of MED is caused by dominant pathogenic variants in COMP (~50% of cases). The remaining 20%-25% of cases are split between MATN3, COL9A1, COL9A2, and COL9A3.
  • Some cases of MED are not caused by pathogenic variants in a known gene [Zankl et al 2007, Unger et al 2008] and remain unclassified.


Exact data about the prevalence of MED and its subtypes are not available. Based on the number of cases seen in growth clinics, rheumatology clinics, or genetics clinics, and compared to conditions whose incidences are more precisely known (e.g., achondroplasia, osteogenesis imperfecta), it seems reasonable to estimate an overall prevalence of 1:20,000 [Unger et al 2008]. This prevalence is most probably an underestimation as several simplex cases (i.e., a single occurrence in a family) may remain undiagnosed. EDM4/rMED is indeed one of the most frequent forms, accounting for almost 25% of all cases of MED [Jackson et al 2012].

Differential Diagnosis

Recessive multiple epiphyseal dysplasia (EDM4/rMED) needs to be distinguished from other multiple epiphyseal dysplasia (MED) types [Unger & Hecht 2001, Ballhausen et al 2003]. Clinical and radiographic differences between the genetically distinct forms of these skeletal dysplasias may allow clinicians to distinguish between them. In contrast to other MED types, prepubertal children with EDM4/rMED usually do not show short stature.

Autosomal dominant forms of MED and their associated proteins and genes:

  • Cartilage oligomeric matrix protein, a glycoprotein of the cartilage extracellular matrix that belongs to the family of extracellular calcium-binding proteins. Pathogenic variants in COMP occur in different autosomal dominant forms of MED (EDM1, OMIM 132400) as well as in the more severe disorder, pseudoachondroplasia. Individuals with MED and COMP pathogenic variants usually have significant involvement at the capital femoral epiphyses and irregular acetabuli [Unger et al 2001].
  • Type IX collagen, a structural component of the extracellular matrix, is a heterotrimer composed of three different chains (alpha-1, alpha-2, and alpha-3) encoded by COL9A1, COL9A2, and COL9A3. Pathogenic variants in individuals with MED have been identified in COL9A2 (EDM2) [Muragaki et al 1996, Holden et al 1999], COL9A3 (EDM3) [Paassilta et al 1999], and COL9A1 [Czarny-Ratajczak et al 2001]. These forms of MED appear to have more severe knee involvement but relative sparing of the hip, resulting in a milder course than the MED associated with COMP or SLC26A2 pathogenic variants [Unger et al 2001].
  • Matrilin 3 (EDM5), an oligomeric protein in the cartilage extracellular matrix. Different pathogenic missense variants in MATN3 were identified in two unrelated families with autosomal dominant MED [Chapman et al 2001]. While it appears to be the mildest form of MED identified to date; EDM5 is associated with a high degree of intrafamilial variability [Mäkitie et al 2004, Zankl et al 2007, Unger et al 2008].

See Epiphyseal dysplasia, multiple: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with recessive multiple epiphyseal dysplasia (EDM4/rMED), the following evaluations are recommended:

  • Height measurement
  • Radiographs of the entire spine (AP and lateral), pelvis (AP), and knees (AP and lateral)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Symptomatic individuals should be seen by a physical therapist and an orthopedist in order to assess the possibility of treatment (physiotherapy for muscular strengthening and maintaining mobility, cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs [NSAIDs]) and the optimal time for surgery (joint replacement), if indicated.

Career counseling is recommended.

Prevention of Secondary Complications

Intensive physiotherapy may help in delaying joint contractures and in maintaining mobility.


Radiographic surveillance by an orthopedist is appropriate.

Agents/Circumstances to Avoid

Sports involving joint overload are to be avoided.

Evaluation of Relatives at Risk

Presymptomatic testing of at-risk relatives is not indicated because no preventive measures or therapeutic interventions to reduce morbidity are available

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women affected by EDM4/rMED may suffer from chronic joint pain which may be increased during pregnancy due to maternal weight gain. Appropriate pain management should be offered and physical therapy should be intensified.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Recessive multiple epiphyseal dysplasia (EDM4/rMED) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry a single copy of a pathogenic variant in SLC26A2. Note: Parental testing is always recommended when pathogenic variants are identified in a proband, in order to confirm the segregation of pathogenic variants in the family and confirm the carrier status of both parents. Results should always be discussed with the family in the context of a genetic counseling consultation.
  • Heterozygous carriers are asymptomatic and have normal stature.
  • No evidence that carriers are at increased risk of developing degenerative joint disease has been presented.
  • To date, de novo pathogenic variants in a proband and germline mosaicism in the parents have not been reported.

Sibs of a proband

  • At conception, each sib of a proband with EDM4/rMED has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband. The offspring of an individual with EDM4/rMED are obligate heterozygotes (carriers) for a pathogenic variant in SLC26A2.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is available on a clinical basis once the pathogenic variants have been identified in the family.

Carrier detection in reproductive partners of heterozygous individuals is available on a clinical basis. The partners can be screened for the four most common pathogenic alleles: p.Arg279Trp, p.Arg178Ter, c.-26+2T>C, and p.Cys653Ser. The risk of carrying a SLC26A2 pathogenic variant is reduced from the general population risk of 1:100 to approximately 1:400 when these four alleles are excluded. If a reproductive partner of a carrier also has an SLC26A2 pathogenic variant, information about genotype-phenotype correlations should be provided to the couple.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Biochemical testing. No data exist on prenatal functional biochemical testing (sulfate incorporation test on chorionic villus or fibroblasts).

Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • MedlinePlus
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
  • MAGIC Foundation
    4200 Cantera Drive #106
    Warrenville IL 60555
    Phone: 800-362-4423 (Toll-free Parent Help Line); 630-836-8200
    Fax: 630-836-8181
  • International Skeletal Dysplasia Registry
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Fax: 310-206-5266

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Multiple Epiphyseal Dysplasia, Recessive: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
SLC26A2 5q32 Sulfate transporter SLC26A2 SLC26A2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Multiple Epiphyseal Dysplasia, Recessive (View All in OMIM)


Molecular Pathogenesis

Pathogenic variants in SLC26A2 (DTDST) are responsible for the family of chondrodysplasias including EDM4/rMED, DTD, ACG1B, and AO2 [Hästbacka et al 1996, Superti-Furga et al 1996a, Superti-Furga et al 1999]. Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans that are not sulfated or are insufficiently sulfated [Superti-Furga 1994, Rossi et al 1997, Rossi et al 1998, Satoh et al 1998], most probably because of intracellular sulfate depletion [Rossi et al 1996]. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impairment of proteoglycan deposition, which is necessary for proper enchondral bone formation [Corsi et al 2001]. A correlation exists between the pathogenic variant, the predicted residual activity of the sulfate transporter, and the predicted severity of the phenotype [Cai et al 1998, Rossi & Superti-Furga 2001, Karniski 2004].

Gene structure. The coding sequence of SLC26A2 is organized in two coding exons separated by an intron of approximately 1.8 kb [Hästbacka et al 1994]. A further untranslated exon is located 5' relative to the two coding exons; it probably has regulatory functions, [Hästbacka et al 1999]. SLC26A2 is expressed in developing cartilage in human fetuses but also in a wide variety of other tissues [Haila et al 2001]. The size of the predominant mRNA species is greater than 8 kb, indicating the existence of significant untranslated sequences [Hästbacka et al 1994, Hästbacka et al 1999]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. The p.Thr689Ser allele has been frequently observed in the heterozygous or homozygous state in several controls of different ethnicity and is thus a common benign variant [Cai et al 1998, Rossi & Superti-Furga 2001].

There is evidence that p.Arg492Trp is a rare benign variant found in seven out of 200 Finnish control individuals and in five out of 150 non-Finnish individuals [Bonafé et al 2008]. This allele may have been erroneously considered pathogenic in previous reports [Rossi & Superti-Furga 2001].

Pathogenic variants. Four pathogenic alleles of SLC26A2 appear to be recurrent: p.Arg279Trp, p.Arg178Ter, c.-26+2T>C, and p.Cys653Ser. Together they represent approximately 70% of the pathogenic variants in SLC26A2.

Most pathogenic variants associated with EDM4/rMED are amino acid substitutions outside transmembrane domains of the sulfate transporter. The p.Arg279Trp variant is the most common pathogenic variant in persons of northern European origin. When homozygous, it results in an EDM4/rMED phenotype; when heterozygous, the phenotype depends on the severity of the pathogenic variant of the second allele (if compounded with a mild pathogenic variant it results in EDM4/rMED, while if compounded with a truncated allele or an amino acid substitution in a transmembrane domain, it results in DTD). Apart from homozygosity for p.[Arg279Trp]+[Arg279Trp] (55% of all EDM4/rMED cases) or for p.[Cys653Ser]+[Cys653Ser] (10%), compound heterozygosity for c.[835C>T] + [-26+2T>C] (10%) and c.[1957T>A ] +[-26+2T>C] (5%) is also common in EDM4/rMED. Other compound heterozygous combinations are also found in EDM4/rMED, most of which include one of the four most common SLC26A2 pathogenic variants (>95% of all individuals with molecularly confirmed EDM4/rMED have at least one of the 4 common SLC26A2 pathogenic variants). There are a few other recurrent pathogenic variants in individuals with EDM4/rMED, including p.Phe256Ser and p.Phe595Leu (neither of which is found in other SLC26A2-related dysplasias).

Distinct phenotypes known to be allelic to EDM4/rMED are diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2), and achondrogenesis 1B (ACG1B).

Table 2.

SLC26A2 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
Benign c.1474C>Tp.Arg492Trp NM_000112​.3
Pathogenic c.-26+2T>C

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. SLC26A2 encodes a sulfate transporter protein of 739 amino acids that is predicted to have 12 transmembrane domains and a carboxy-terminal, cytoplasmic, moderately hydrophobic domain [Hästbacka et al 1994]. This protein transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. The sulfate transporter protein belongs to the family of sulfate permeases. The overall structure with 12 membrane-spanning domains is shared with two other human anion exchangers: PDS (OMIM 274600), a chloride-iodide transporter involved in Pendred syndrome, and CLD, which is responsible for congenital chloride diarrhea. The function of the carboxy-terminal hydrophobic domain of the sulfate transporter is not yet known.

Abnormal gene product. Most of the SLC26A2 pathogenic variants either predict a truncated polypeptide chain or affect amino acids that are located in transmembrane domains or are conserved in man, mouse, and rat. Individuals homozygous for the "Finnish" pathogenic variant c.-26+2T>C have reduced levels of mRNA with intact coding sequence. Thus, the variant presumably interferes with splicing and/or further mRNA processing and transport [Hästbacka et al 1996, Hästbacka et al 1999].

The p.Arg178Ter pathogenic variant was shown to abolish sulfate transporter activity in a Xenopus oocyte model [Karniski 2001].


Literature Cited

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  • Bonafé L, Hästbacka J, de la Chapelle A, Campos-Xavier AB, Chiesa C, Forlino A, Superti-Furga A, Rossi A. A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia. J Med Genet. 2008;45:827–31. [PMC free article: PMC4361899] [PubMed: 18708426]
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  • Chapman KL, Mortier GR, Chapman K, Loughlin J, Grant ME, Briggs MD. Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia. Nat Genet. 2001;28:393–6. [PubMed: 11479597]
  • Corsi A, Riminucci M, Fisher LW, Bianco P. Achondrogenesis type IB: agenesis of cartilage interterritorial matrix as the link between gene defect and pathological skeletal phenotype. Arch Pathol Lab Med. 2001;125:1375–8. [PubMed: 11570921]
  • Czarny-Ratajczak M, Lohiniva J, Rogala P, Kozlowski K, Perala M, Carter L, Spector TD, Kolodziej L, Seppanen U, Glazar R, Krolewski J, Latos-Bielenska A, Ala-Kokko L. A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet. 2001;69:969–80. [PMC free article: PMC1274373] [PubMed: 11565064]
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  • Haila S, Hästbacka J, Bohling T, Karjalainen-Lindsberg ML, Kere J, Saarialho-Kere U. SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types. J Histochem Cytochem. 2001;49:973–82. [PubMed: 11457925]
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  • Hästbacka J, Kerrebrock A, Mokkala K, Clines G, Lovett M, Kaitila I, de la Chapelle A, Lander ES. Identification of the Finnish founder mutation for diastrophic dysplasia (DTD). Eur J Hum Genet. 1999;7:664–70. [PubMed: 10482955]
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Chapter Notes

Revision History

  • 23 January 2014 (me) Comprehensive update posted live
  • 18 March 2010 (me) Comprehensive update posted live
  • 27 December 2006 (me) Comprehensive update posted live
  • 20 July 2004 (me) Comprehensive update posted live
  • 29 August 2002 (me) Review posted live
  • 25 February 2002 (db) Original submission
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