A novel MTX2 gene splice site variant resulting in exon skipping, causing the recently described mandibuloacral dysplasia progeroid syndrome

Abstract

Until recently, mandibuloacral dysplasia (MAD) with type A and type B lipodystrophy was the first to come to mind in the association of mandibular hypoplasia, lipodystrophy, and acro‐osteolysis. However, it has recently been added to the differential diagnosis of MAD, a newly defined syndrome, called MDPS. MDPS is a skeletal dysplasia characterized by postnatal growth retardation, hypotonia, generalized lipodystrophy, skin changes, progeroid traits, and dysmorphic facial features, including prominent eyes, long pinched nose, mandibular hypoplasia, and a small mouth. Biallelic null variants of the MTX2 gene are responsible for this syndrome. We performed whole‐exome sequencing (WES) in a 6‐year‐old patient with skeletal dysplasia. WES revealed a novel homozygous c.543+1G>T splice site variant in the MTX2 gene. We also extracted total RNA from peripheral blood and used reverse transcription‐polymerase chain reaction to generate cDNA. Sanger sequencing from cDNA showed that exon 8 of MTX2 was skipped. This study adds to the genetics and phenotype of MDPS and underlines the importance of comprehensive clinical and molecular research.

Case report: A novel splice-site mutation of MTX2 gene caused mandibuloacral dysplasia progeroid syndrome: the first report from China and literature review

“…The ‘Beaten silver’ skull observed on the skull radiograph of the MADaM patient reported by Yeter Doğan et al. ( 12 ), may be related to increased intracranial pressure caused by cranial suture atresia, which was not found in our patient.…”

“…MADaM, like other types of MAD, also shown as autosomal recessive, and the patients reported so far are all homozygous mutations in the MTX2 gene, which may be related to their consanguineous family history ( 11 , 12 ). The clinical symptoms of MADA typically appeared at the age of 4-5 years, with most cases being partial lipodystrophy in the torso and limbs.…”

“…MTX2 located on chromosome 2q31.1, consists of 263 amino acids and contained two functional domains: Sam37/metaxin_N domain (41-162AA) and glutathione S-transferase (GST) domain (187-249AA) ( https://www.ebi.ac.uk/interpro/protein/UniProt/O75431 ). The six previously reported MTX2 variants in MADaM patients are summarized in Figure 2B , all variants were homozygous and from six consanguineous families ( 11 , 12 ). There were three splicing mutations, two frameshift mutations, and one missense mutation.…”

“…Delayed closure of the cranial suture, clavicle hypoplasia and thin ribs due to osteolysis, acral osteolysis, joint contracture and nail dysplasia are common in almost all MAD cases ( 2 ). Dysplasia of the femoral head is rarely reported and has been reported in 6/7 of MADaM cases ( 11 , 12 ). Occipital ossification defect is thought to be a unique feature of MADB ( 17 ), showing fragmented ossification on cranial imaging, which has not been found in MADaM to date.…”

“…MADaM is clinically characterized by mandibuloacral dysplasia, generalized lipodystrophy, hypotonia, acro osteolysis, skin abnormalities, renal impairment, and cardiovascular system damage such as hypertension and left ventricular hypertrophy. To date, only 2 studies have reported 7 genetically definite diagnosed MADaM ( 11 , 12 ). This study is the third, and the first MADaM from China.…”