A novel missense ATRX gene mutation in one family with Alpha-thalassemia and Mental retardation-hypotonic facies syndrome

Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder that affects many parts of the body. This condition occurs almost exclusively in males and everyone with this syndrome has distinctive facial features. Also, most affected individuals have mild signs of alpha thalassemia. This syndrome caused by mutations in the ATRX gene. The ATRX gene provides instructions for making a protein that plays an essential role in normal development. This gene helps regulate the expression of other genes through a process known as chromatin remodeling. Also the ATRX protein appears to regulate the expression of two genes, HBA1 and HBA2, that are necessary for the production of hemoglobin.One family with 13 weak pregnancies and one deceased affected boy was referred to the molecular genetic department of Sarem hospital. The affected boy had microcephaly, neurodevelopmental delay, mental retardation, craniosynostosis, trigonocephaly, hypertelorism, cryptorchidism, ambiguous genitalia, abnormal facial shape, and joint stiffness among other features and alpha thalassemia hematologic indexes. Parents are consanguine and don’t have other affected sibling. Previously negative diagnostic tests in proband were MPLA for microdeletion/microduplication syndromes and whole-genome oligo array CGH. Finally, WES performed and results showed one hemizygote variant of uncertain significance (VUS) in ATRX gene and one heterozygote VUS in COL4A43BP gene. Variants confirmation performed on parents’ genomic DNA and results suggest ATRX gene alternation that transmits from mother can be the causative mutation in this family.In the next step we performed PND for the fetus of this family and results reveled hemizygote variant of ATRX gene and affected feature. Segregation analysis was performed on a large number of individuals in this family (in mother and her husband, as well as her father, mother, brother, and uncle) and the absence of this variant in normal male as well as normal individuals provide de novo and likely pathogenic evidence for this variant according to the ACMG and Sherlock complementary guides.

کلیدواژه ها:

Alpha thalassemia X-linked Intellectual Disability Syndrome ، Variant of Uncertain Significance ، Likely Pathogenic. Segregation Analysis ، ATRX Gene