Pathogenic variants in MECP2 cause a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT; 312750). Although historically this was considered an X-linked dominant diagnosis with male lethality, it is now known that males can also be affected, with a disease spectrum ranging from severe neonatal encephalopathy to intellectual disability (ID). Other features commonly seen in RTT are inconsistently present in males. A qualified genotype-phenotype correlation exists, with variants that are known to cause RTT in females most often leading to more severe phenotypes in males. Additionally, whereas pathogenic MECP2 variants identified in affected females with classic and atypical RTT are most often de novo variants, pathogenic variants in males may be either de novo or maternally inherited. Here we report 4 novel families with pathogenic MECP2 variants. In all 4 families, the affected probands were male and maternal inheritance was identified. Family 1: The proband is a now 8-year-old male with mild global developmental delay, epilepsy, ataxia, and hypotonia. He also has significant anxiety. Epilepsy gene panel identified a hemizygous pathogenic variant in MECP2 (c.491C>T; p.Ala140Val); targeted testing confirmed maternal inheritance. His mother has no significant medical issues or learning issues, but endorses a history of anxiety. He has four clinically unaffected siblings; one brother has been tested and is negative. His other brother and sisters have not been tested. Family 2: The proband is a now 47-year-old male with mild-moderate intellectual disability. Genetic testing was initiated after MRI performed in the context an episode of confusion and shaking concerning for a panic attack revealed signal abnormalities in the bilateral cerebral peduncles possibly concerning for Fragile X Associated Tremor Ataxia Syndrome (FXTAS). He also experienced a motor regression and onset of dystonia after an episode of rhabdomyolysis in his mid 40’s and has not returned to baseline. Trio exome sequencing identified a maternally inherited hemizygous pathogenic variant (c.499C>T; p.Arg167Trp) in MECP2. Cascade testing identified that his sister and niece also both carry the familial MECP2 variant. His sister has a history of learning difficulties, significant anxiety, obsessive compulsive disorder, and has developed progressive spasticity with hyperreflexia and sustained clonus over time. His niece also has anxiety, obsessive compulsive disorder, and bipolar disorder. Family 3: The proband is a now 37-year-old male with mild intellectual disability and autism spectrum disorder. He also has a history of anxiety and depression. Trio exome sequencing identified a maternally inherited hemizygous pathogenic variant (c. 1136_1151del16; p.Pro379HfsX25) in MECP2. Testing was initiated after the onset of abnormal movements in his thirties suggestive of dystonia. Exam was notable for kyphosis and shuffling gait. His mother reports a history of anxiety, but no learning or cognitive concerns and no other neurologic symptoms. He has one clinically unaffected sister who has not yet been tested. Exome sequencing also identified a de novo, heterozygous c.1672C>T (p.Arg558Cys) variant of uncertain significance in ALDH18A1, though it is unclear whether or not this is contributing to his phenotype. Family 4: The proband is a now 8-year-old male who initially presented for evaluation due to concern for global developmental delay, hypotonia, and macrocephaly. Family history was unremarkable. MRI identified prominent perivascular spaces. Trio exome sequencing identified a maternally inherited likely pathogenic hemizygous variant (c.1244delC; p.Pro415LeufsX6) in MECP2. The proband’s younger brother subsequently presented with expressive language delay and was also macrocephalic. Targeted testing confirmed the presence of the familial MECP2 variant. These 4 familial reports of pathogenic MECP2 variants add to the data provided by previous publications describing the phenotypic spectrum in affected males and supporting that many of the variants may be maternally inherited. Affected male probands in all cases presented with developmental delay and/or intellectual disability. Only 1/4 probands had epilepsy. Anxiety was present in 3/4. Cascade testing identified carrier female relatives with a prominent neuropsychiatric phenotype in one family. Anxiety was also reported in the mothers of two other families, without any other cognitive or neurologic features. Although two families harbored pathogenic missense variants previously known to be associated with an X-linked intellectual disability phenotype, two families with mildly affected male probands and unaffected female carrier mothers had novel, predicted loss of function variants that would have been expected to result in a RTT phenotype. These families highlight the clinical variability that can be seen with pathogenic MECP2 variants and challenge reported genotype-phenotype correlations, providing important information for genetic counseling.
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Feb 10, 2023
Aino M Jaakkola + 1
Open Access