Mapping of the autosomal recessive (AR) craniometaphyseal dysplasia locus to chromosome region 6q21-22 and confirmation of genetic heterogeneity for mild AR spondylocostal dysplasia

Abstract

We report on a four-generation inbred family including 10 individuals affected with a form of craniotubular dysplasia (CTD). All affected patients were born to consanguineous healthy parents; this finding, together with the equal sex ratio among affected individuals and the occurrence of only normal individuals among their offspring, indicates that the disease in this family is an autosomal recessive (AR) trait. Taking into account the segregation pattern of the disease in the family and the radiological characteristics of two young CTD patients, the most likely diagnosis for the defect is AR craniometaphyseal dysplasia (CMD). CMD is a CTD, with both autosomal dominant (AD) and recessive forms. The description of the present genealogy confirms the AR pattern of inheritance of some cases of CMD and contributes to a better delineation of the clinical spectrum of AR CMD, suggesting a more pronounced diaphyseal involvement in the AR compared with the AD CMD. Through genomewide scanning, we mapped the AR CMD to a 7 cM interval, between D6S302 and D6S1639, at 6q21-22 region. We have also excluded the positional candidate COL10A1 gene as being the responsible for this disorder. Curiously, a form of AR spondylocostal dysplasia (SD) also segregates in the family, including one affected individual with both conditions. The gene DLL3, mapped to 19q13 region, was recently found to be responsible for one form of AR SD; however, we did not find evidence of linkage between this 19q region and the SD segregating in our family, thus implying in genetic heterogeneity for AR SD.

Cochlear developmental defect and background-dependent hearing thresholds in the Jackson circler (jc) mutant mouse

“…The human chromosomal region that is homologous to the jc minimal genetic interval is present at 6q21. Craniometaphyseal dysplasia (OMIM 218400), which is a recessive syndrome characterized by cranial deformities including hearing loss, is among several human conditions that have been linked to the 6q21 region (Iughetti et al, 2000). However marker D6S302, which defines the centromeric border of the linked interval, is located 4 Mb telomeric to the recombinant jc marker D10Ntra118 excluding this syndrome as the human jc disease homolog.…”

Recent progress in the molecular genetics of sclerosing bone dysplasias

“…Besides the initially described severe recessive form, a milder autosomal dominant form has been recognized [42]. In the recessive form the involvement of the diaphyses is more pronounced and craniometadiaphyseal dysplasia would have been more precise nomenclature [43]. Genetic linkage studies localized the gene for the recessive form to chromosome 6q21-22 whereas the dominant form maps to chromosome 5p15.2-p14.2 [43,44].…”

“…In the recessive form the involvement of the diaphyses is more pronounced and craniometadiaphyseal dysplasia would have been more precise nomenclature [43]. Genetic linkage studies localized the gene for the recessive form to chromosome 6q21-22 whereas the dominant form maps to chromosome 5p15.2-p14.2 [43,44]. Recently the ANK gene was proven to underly the dominant form [45,46].…”

A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal Dysplasia

“…Some pedigrees suggest an autosomal recessive (AR) mode of transmission [1,18,19,20,21] and a linkage study has identified a potential locus for the autosomal recessive form of CMD within a 7 cM interval on chromosome 6q21-22 [18]. However, a causative variant responsible for AR CMD could not be identified.…”