Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population

Abstract

Barbosa M, Sousa AB, Medeira A, Lourenço T, Saraiva J, Pinto‐Basto J, Soares G, Fortuna AM, Superti‐Furga A, Mittaz L, Reis‐Lima M, Bonafé L. Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population. SLC26A2‐related dysplasias encompass a spectrum of diseases: from lethal achondrogenesis type 1B (ACG1B; MIM #600972) and atelosteogenesis type 2 (AO2; MIM #256050) to classical diastrophic dysplasia (cDTD; MIM #222600) and recessive multiple epiphyseal dysplasia (rMED; MIM #226900). This study aimed at characterizing clinically, radiologically and molecularly 14 patients affected by non‐lethal SLC26A2‐related dysplasias and at evaluating genotype–phenotype correlation. Phenotypically, eight patients were classified as cDTD, four patients as rMED and two patients had an intermediate phenotype (mild DTD – mDTD, previously ‘DTD variant'). The Arg279Trp mutation was present in all patients, either in homozygosity (resulting in rMED) or in compound heterozygosity with the known severe alleles Arg178Ter or Asn425Asp (resulting in DTD) or with the mutation c.727‐1G>C (causing mDTD). The ‘Finnish mutation’, c.‐26+2T>C, and the p.Cys653Ser, both frequent mutations in non‐Portuguese populations, were not identified in any of the patients of our cohort and are probably very rare in the Portuguese population. A targeted mutation analysis for p.Arg279Trp and p.Arg178Ter in the Portuguese population allows the identification of approximately 90% of the pathogenic alleles.

Recessive MED with auricular swelling due to compound heterozygosity Arg279Tpr/Thr512Lys in the SLC26A2 gene

“…When heterozygous it usually results in DTD or sometimes in an intermediate phenotype (mild DTD–rMED; Table ). It has been estimated that 60% of typical rMED patients are homozygous for this mild mutation [Bonafé et al, ; Barbosa et al, ]. c.862C > T (p.Arg279Tpr) is located in the extracellular loop and DTDST transporters bearing this mutation have significant (39–62%) residual activity when compared to the wild type [Karniski, ].…”

A compound heterozygote SLC26A2 mutation resulting in robin sequence, mild limbs shortness, accelerated carpal ossification, and multiple epiphysial dysplasia in two Brazilian sisters. A new intermediate phenotype between diastrophic dysplasia and recessive multiple epiphyseal dysplasia

“…Mutations in SLC26A2 gene result in a continuum clinical spectrum of autosomal recessive chondrodysplasias that include, in increasing order of severity, the lethal achondrogenesis type IB (ACG‐1B; OMIM 600972) and atelosteogenesis type II (AO‐II; OMIM 256050); the diastrophic dysplasia (DTD; OMIM 222600) and the recessive multiple epiphyseal dysplasia (rMED; OMIM 226900). Affected individuals with a more mildly DTD phenotype have been described and they have been classified as DTD variant or as intermediate phenotype between DTD and rMED [Horton et al, ; Czarny‐Ratajczak et al, ; Dwyer et al, ; Barbosa et al, ]. Other cases with phenotypic DTD variant, secondary to mutations in SLC26A2 , overlapping to Desbuquois dysplasia [OMIM 251450], were described and suggested a locus heterogeneity for Desbuquois dysplasia [Miyake et al, ; Panzer et al, ].…”

“…The severity of the phenotypes related to SLC26A2 mutation has been correlated with the residual activity of sulfate transporter resulting of the different types of mutations [Hästbacka et al, ; Karniski, ; Rossi and Superti‐Furga, ]. Literature data have shown that homozygous for null mutation lead to phenotype of ACG‐1B [Karniski, ; Rossi and Superti‐Furga, ]; that compound heterozygous to a null mutation and to a mutation with some residual activity can result in AO‐II, DTD or DTD variant [Hästbacka et al, ; Karniski, ; Rossi and Superti‐Furga, ; Maeda et al, ; Czarny‐Ratajczak et al, ; Dwyer et al, ; Barbosa et al, ], and that homozygous or compound heterozygous mutations with significant residual activity (“mild” mutations) result in rMED [Superti‐Furga et al, ; Karniski, ; Ballhausen et al, ; Mäkitie et al, ; Cho et al, ; Hinrichs et al, ; Barbosa et al, ]. It has also been showed that the “Finnish founder mutation” (c.−26 + 2T>C) acts by severely reduced mRNA levels, but not abolish gene function completely [Hästbacka et al, ] and, that the homozygosis or compound heterozygosity for this mutation can result in variable phenotypes that include AO‐II, DTD, DTD variant or rMED [Hästbacka et al, ; Ballhausen et al, ; Dwyer et al, ].…”

SLC26A2 disease spectrum in Sweden – high frequency of recessive multiple epiphyseal dysplasia (rMED)

“…A Portuguese study on non-lethal DTD-related disorders found at least one Arg279Trp mutation in every patient, while none had IVS1+2T>C (13). Our study shows that the Finnish SLC26A2 founder mutation is overrepresented as compared with other cohorts outside Finland.…”