Differences in sex development

Gene: ATRX

Looking at mode of inheritance:

Associated with Alpha-thalassemia/mental retardation syndrome #301040 (XLD) and Mental retardation-hypotonic facies syndrome, X-linked #309580 (XLR) in OMIM, both of which have mention of genital abnormalities.

A female patient is reported in PMID: 16955409 (Badens et al 2006) with typical features of typical features of ATRX syndrome including severe developmental delay with bad eye contact and marked truncal hypotonia, dysmorphic features including severe microcephaly. Genital anomalies with hypoplasia of labia majora and minora were also noted. A de novo heterozygous R246C (c.951C > T) missense mutation located in the ATRX was identified. A skewed X-inactivation pattern was found.

PMID: 16100724 (Wada et al 2005) report a female carrier (V194A in ATRX) with moderate mental retardation, but genital abnormalities are not mentioned. She was the mother of a son with α-thalassemia/mental retardation syndrome. A non-skewed pattern of X inactivation was found in this female.

PMID: 1415255 (Gibbons et al 1992) looked at x inactivation in 7 families that included individuals with the ATR-X syndrome. They found that intellectually normal female carriers could be identified by the presence of rare cells containing Hb H inclusions in their peripheral blood and by an extremely skewed pattern of X inactivation in cells from a variety of tissues. Genital abnormalities are not mentioned.

Created: 1 Jul 2021, 2:15 p.m. | Last Modified: 1 Jul 2021, 2:15 p.m.

Panel Version: 2.48

Green List (high evidence)

As discussed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green.

Created: 29 Apr 2019, 9:46 a.m.

Comment when marking as ready: Associated with phenotype in OMIM and as a confirmed G2P. At least 8 variants reported.

Created: 10 Apr 2017, 9:29 a.m.

Comment on phenotypes: Microcephaly, intellectual disability, genital anomalies. Variants also associated with Alpha-thalassemia/mental retardation syndrome 301040 (XLD) and Alpha-thalassemia myelodysplasia syndrome, somatic 300448

Created: 10 Apr 2017, 9:28 a.m.

Green List (high evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Microcephaly, intellectual disability, genital anomalies

Publications

• Gene reviews: https://www.ncbi.nlm.nih.gov/books/NBK1449/

Variants in this GENE are reported as part of current diagnostic practice