Homozygous deletion ofMYADML2in cranial asymmetry, reduced bone maturation, multiple dislocations, lumbar lordosis, and prominent clavicles

A null mutation in a patient can facilitate phenotype assignment and uncovers the function of that specific gene. We present five sibs of a consanguineous Pakistani family afflicted with a new syndrome with an unusual combination of skeletal anomalies including cranial asymmetry, fused sagittal sutures deviating from the medial axis, mandibular prognathia, maxillary hypoplasia, misaligned and crowded teeth, delayed bone age, multiple dislocations, hypoplastic and malpositioned patellae, humeral intracondylar fissures, scapular dyskinesis, long limbs, lumbar lordosis, protruding chest, prominent clavicles, short 5th digital rays, and ventral transverse digital creases plus features of cutis laxa. We mapped the disease gene locus to a 3.62-Mb region at 17q25.3 and identified a homozygous deletion of maximal 7.3 kb deduced to totally inactivateMYADML2and downstream genePYCR1, biallelic variants in which cause autosomal recessive cutis laxa (ARCL). All five affected sibs had the most common features of ARCL but not many of the less common ones. We attributed the anomalies not typical for ARCL to MYADML2 deficit, because no other genetic defect possibly a candidate to underlie the skeletal phenotype was found.MYADML2is a gene of unknown function, has not been studied, and has not been associated with disease. Our findings present a possible phenotype for MYADML2 deficit that includes impaired bone patterning and maturation, definitely show that the gene is not essential for survival, and provide a start point for future studies on the function of MYADML2 protein. Detection of new patients is needed to confirm and delineate MYADML2-deficiency phenotype.

Automated summary

The study identified a new syndrome in a consanguineous Pakistani family involving various skeletal anomalies. Through gene mapping, a homozygous deletion in MYADML2 was found to be associated with specific features of the disorder, providing insight into the gene's potential role in bone patterning and maturation. Further research is needed to confirm and expand on the phenotype associated with MYADML2 deficiency.