Spondylocostal Dysostosis 5

A number sign (#) is used with this entry because of evidence that spondylocostal dysostosis (SCDO5) is caused by heterozygous or compound heterozygous mutation in the TBX6 gene (602427) on chromosome 16p11.

For a general phenotypic description and a discussion of genetic heterogeneity of spondylocostal dysostosis, see SCDO1 (277300).

Clinical Features

Rimoin et al. (1968) reported a family in which father and son and probably 2 preceding generations were short of stature (less than 5 feet), the shortening being mainly in the trunk, and had multiple rib and vertebral anomalies. The number of ribs was reduced to 11 and several ribs were fused posteriorly. Hemivertebra and vertebral fusion were noted at multiple levels in the cervical and thoracic spine. No neurologic manifestations were present. Langer (1967) reported another family with multiple affected generations.

Rutt and Degenhardt (1959) described a 4-generation family (Familie Mck.) in which 4 individuals had congenital scoliosis. Van der Sar (1952) found multiple hemivertebrae and rib anomalies in a mother and daughter.

Ayme and Preus (1986) did a cluster analysis on reported cases of spondylocostal dysostosis, spondylothoracic dysplasia, and Jarcho-Levin syndrome. They concluded that the dominant and mild recessive forms of spondylothoracic dysplasia, falling into their cluster 2, could not be distinguished.

The family with affected members in 3 generations reported by Temple et al. (1988) may have had the same condition as that reported by Rimoin et al. (1968) and others. Short stature was striking. The rib changes were only mild.

Lorenz and Rupprecht (1990) reported the cases of a father and daughter. Abnormality of the ribs was more severe in the infant daughter than usual in this form and was suggestive of the changes found in the autosomal recessive type.

Gucev et al. (2010) studied an indigenous 3-generation Macedonian family segregating autosomal dominant spondylocostal dysostosis. The 12-year-old proband and his father and paternal uncle had disproportionately short trunks and necks with a normal range of movement, and radiographs revealed mild scoliosis with a mixture of hemivertebrae and vertebral blocks. The ribs were relatively mildly affected, with nearly normal alignment and a possible point of fusion high on the left posteriorly in the proband and mild thoracic sulci and flaring of the lower rib cage in the father and uncle. There were no other significant organ abnormalities, no obvious dysmorphic features, and neurodevelopment was normal. The paternal grandfather was deceased but was reported to have had the same phenotype.

Wu et al. (2015) reported 23 Han Chinese individuals with a diagnosis of congenital scoliosis that was related to compound heterozygous mutation in the TBX6 gene. All 23 individuals had 1 or more hemivertebrae. The number of hemivertebrae was significantly higher in patients with TBX6-related congenital scoliosis that in those with congenital scoliosis without TBX6 mutation. Rib abnormalities were also reported in most patients.

Liu et al. (2019) studied cohorts of patients with congenital scoliosis (CS), 345 from China (cohort 1), 142 from Japan (cohort 2), and 10 from the United States (cohort 3). Clinically measurable endophenotypes were compared according to the TBX6 genotypes. Liu et al. (2019) developed a clinical diagnostic algorithm (TACScore) to assist in clinical recognition of TBX6-associated CS (TACS). Cohort 1 included 33 TACS patients, and these were significantly younger at onset (median age 2 years) than the remaining CS patients (median age 3 years), presented with 1 or more hemivertebrae/butterfly vertebrae, and exhibited vertebral malformations involving the lower part of the spine (T8-S5); observations were confirmed in Japanese and US cohorts. Simple rib anomalies were prevalent in the TACS patients (present in 25 of 33) while intraspinal anomalies were uncommon (present in only 1 patient). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9.

Inheritance

The inheritance pattern of spondylocostal dysostosis-5 can be autosomal dominant (Sparrow et al., 2013) or autosomal recessive (Wu et al., 2015).

Liu et al. (2019) pointed out that TACS does not follow conventional rare variant mendelian inheritance expectations, likely reflecting the embryonic lethality of TBX6 homozygous null alleles. Instead, TACS is caused by biallelic variants at a locus, consistent with autosomal recessive trait manifestation, but with the presence a single rare loss-of-function variant in trans with one common hypomorphic allele; a gene dosage that is less than haploinsufficieny but not 0, as with homozygous null alleles. Liu et al. (2019) suggested that this genetic model (compound inheritance and TACS) may provide an explanation for scenarios in which monoallelic variants and phenotypes are perceived to be following a dominant inheritance pattern, but for a disease trait with incomplete penetrance, or in which the disease pattern observed is pseudodominance, as found when the carrier state occurs at a high frequency in the population. Because the T-C-A haplotype is common worldwide (44% among Asians and 33% among Europeans, but less than 1% among Africans), the haplotype is likely to be parsed and filtered out by genomic analytical pipelines.

Cytogenetics

Polydysspondyly was described by Turpin et al. (1959) in association with a translocation involving group D and G chromosomes. De Grouchy et al. (1963) reported a similar condition in mother and daughter, both of whom carried a 14-15 translocation.

Molecular Genetics

In 3 affected and 2 unaffected members of the 3-generation Macedonian family with autosomal dominant spondylocostal dysostosis, originally described by Gucev et al. (2010), Sparrow et al. (2013) performed whole-exome sequencing and identified a heterozygous mutation in the TBX6 gene (602427.0001) that segregated with the disease in the family. The mutation disrupts the natural stop codon, resulting in a mutant protein with approximately half the transcriptional activation activity of wildtype TBX6.

Wu et al. (2015) identified a total of 23 individuals with congenital scoliosis in discovery and replication samples of Han Chinese individuals who carried a null allele of TBX6 (e.g., 602427.0002) and a common 3-SNP haplotype as the second TBX6 allele (602427.0003). The null alleles comprised 16p11.2 deletions affecting TBX6, a nonsense mutation, and frameshift mutations. From an independent series of 42 Han Chinese patients with a 16p11.2 deletion, Wu et al. (2015) identified 6 persons with congenital scoliosis, 5 of whom (83%) had the phenotype explained by TBX6 compound inheritance (p = 0.004). In vitro functional assays suggested that the haplotype functions as a hypomorphic allele.

Among 26 patients from the 3 cohorts (newly reported patients from cohorts 1 and 2, and all patients in cohort 3) reported by Liu et al. (2019), all but 3 had a 16p11.2 deletion on the first allele. All but 2 of these 26 patients had the TCA risk haplotype on the second allele. One Hispanic patient carried a c.853C-T variant, which was novel in European populations and predicted to deleterious by PolyPhen and SIFT; the allele of the other patient, a Caucasian female, was given as 'NA.'

Exclusion Studies

In a 3-generation Macedonian family segregating autosomal dominant spondylocostal dysostosis, Gucev et al. (2010) analyzed the 4 genes known to cause recessive forms of SCDO (see 277300) but found no mutations.

Nomenclature

The terms dysostosis and dysplasia are used here interchangeably. Both words refer to abnormal development or formation.

Animal Model

Liu et al. (2019) generated a TBX6 gene-edited mouse model for compound inheritance, with loss-of-function and mild hypomorphic (mh) alleles. Gene expression in vitro was downregulated by the Tbx6(mh) allele mutant to approximately 65% of the wildtype gene, close to the 70% dosage level of the human TBX6 mild hypomorphic allele. As predicted and consistent with literature observation, no homozygotes for the loss-of-function variant were identified in liveborn animals, and expected mendelian ratios of particular genotypic combinations were distorted in liveborns, consistent with embryonic lethality in Tbx6-null animals. Liu et al. (2019) phenotypically assessed mice with 5 specific Tbx6 genotypes: homozygous wildtype, heterozygous wildtype/null, heterozygous wildtype/mh, homozygous mh, and heterozygous null/mh. Consistently, only the null/mh mice exhibited vertebral malformations. Similar to human, all Tbx6 null/mh mice had vertebral malformations involving the lower part of the spine. Defects of vertebral column formation were present in most of the null/mh mice. The recapitulation of the type, extent, and distribution of vertebral malformations in the engineered compound inheritance model in mice further supported the compound inheritance and gene dosage model for TACS and implicated the biologic perturbations in vertebral column malformations in this type of congenital scoliosis.