The patient was referred to the medical genetics center because of language delay and deficit and family history of autism (Asperger's), without any suspicion or clinical features of Mesomelia-Synostosis. Karyotype analysis was performed for research and identified an apparently balanced translocation between chromosomes 1 and 8, FISH analysis was performed for better characterization of the breakpoints and identification of possible deletions or duplications in the region. Microarray analysis showed no gain or loss involving chromosomes 1 and 8, confirming a balanced translocation.
Once a balanced translocation is confirmed and since it is known that the region where the break occurred on chromosome 8 (q13.3/q21) is a region of interest for investigating Mesomelia-Synostosis was performed mate-pair technique for sequencing the breakpoint regions, where an intragenic break in SLCO5A1 and integrality of SULF1 was identified.
Both genes are located in the 8q13.3 region. The SULF1 gene is a protein coding gene for the enzyme sulfatase 1 that acts as a cellular signaling agent, impacting on the growth and differentiation of various tissues(13). The downregulation of this gene may be related in different types of cancer, such as hepatocellular cancer, ovarian, and breast cancer(14).
SLCO5A1 (Solute Carrier Organic Anion Transporter Family Member 5A1) is a protein coding involved in transporter activity(15). Their expression is detected in various tissues under healthy conditions, such as brain, heart, skeletal muscle, ovary and breast, being overexpressed in skeletal muscle and heart. It has also been observed in bone tumors and in prostate and breast cancers(16).
Until 2017 five patients with MMS had been described in the literature with microdeletions in the 8q13 region, with variations from 582 kb to 738 kb but always involving loss of function in both SULF1 and SLCO5A1 genes (9, 10, 17, 18).
Dardis et al, 2019 reported a case of a patient with MMS who did not have a deletion in the 8q13 region like the other patients described to this point, but presented a monoallelic expression of SULF1 led to haploinsufficiency of this gene causing its loss of function. No alterations were found in SLCOA1, or in any other gene of importance(12).
Although both are expressed in skeletal tissues, SULF1 is the candidate to have more influence regarding the triggering of skeletal abnormalities associated with MSS, since the study by Ratzka, et al demonstrated that mutations for SULF1 resulted in reduced bone length, early ossification of vertebrae, and fusion of the vertebrae with tail vertebrae in mouse model (19), which also corroborates with the findings of Daris et al.