Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males

doi:10.1016/S0140-6736(00)02661-1

The Lancet

Volume 356, Issue 9232, 2 September 2000, Pages 830-832

https://doi.org/10.1016/S0140-6736(00)02661-1 Get rights and content

Summary

Rett syndrome is a cause of severe learning disability in girls and is associated with a characteristic history and movement disorder. It is an X-linked dominant condition associated with mutations of the MECP2 gene on the distal part of the X-chromosome. If present in a male conceptus, the mutation is usually lethal. We present evidence to show that males can be affected by Rett syndrome. In the boy presented, this situation came about because cells containing the MECP2 mutation existed alongside a normal cell line. Somatic mosaicism could explain the occurrence of other X-linked dominant disorders in males, when they would normally be lethal.

References (5)

C Schanen et al.
A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map
Am J Hum Genet
(1998)
A Clarke
Rett Syndrome
J Med Genet
(1996)

There are more references available in the full text version of this article.

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Somatic copy number variants in neuropsychiatric disorders
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Copy number variants (CNVs) have been implicated in neuropsychiatric disorders, with rare-inherited and de novo CNVs (dnCNVs) having large effects on disease liability. Recent studies started exploring a class of dnCNVs that occur post-zygotically, and are therefore present in some but not all cells of the body. Analogous to conditional mutations in animal models, the presence of risk mutations in a fraction of cells has the potential to enlighten how damaging mutations affect cell-type/cell-circuit specific pathologies leading to neuropsychiatric manifestations. Although mosaic CNVs appear to contribute to a modest fraction of risk (0.3−0.5%), expanding our insights about them with more sensitive experimental and statistical methods, has the potential to help clarify mechanisms of neuropsychiatric disease.
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There are no two identical human genomes in the world; even between the genomes of monozygotic twins it is possible to find differences. Moreover, the human genome is not unique and we experience many changing genomes during our lifetime. This nonuniqueness rests on different types of genetic variants. Single nucleotide variants (SNVs), copy number variants (CNVs), inversions, translocations, microchimerism, and revertant mosaicism are all names associated with this genomic divergence. If this variability has arisen before us, it is called germline, inherited, or seemingly de novo. If it has it arisen after us, it is called somatic mosaicism or true de novo. Two typical human genomes can vary by a few million SNVs and a few hundred CNVs, whereas as a consequence of lifetime mutational events two of our genomes might differ from one another, albeit at a much lower rate, on SNVs, CNVs, and other variations as well. Our health depends on this massive amount of variability.
Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort
2019, Genetics in Medicine
Citation Excerpt :
The rate of somatic mosaic in males (16.7%, 3/18) was significantly higher than that in females (0.4%, 2/453) (p = 0.0004492, odds ratio = 43.47 [95% CI 6.33 – inf] by a two-tailed Fisher’s exact test). Among different studies, 69% (9/13) of reported RTT mosaic patients were male.8-15 The application of mosaicism screening had a significant impact on the genetic diagnosis of RTT males.
To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders.
We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting MECP2, CDKL5, and FOXG1 was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic MECP2 variants was further quantified.
Pathogenic variants of MECP2/CDKL5/FOXG1 were found in 324/471 (68.7%) patients. Somatic MECP2 mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic MECP2 mosaicism had mosaicism at MECP2-Arg106. Germline MECP2 mosaicism was detected in 5/21 (23.8%) fathers.
This is the first systematic screening of somatic and paternal germline MECP2 mosaicism at a cohort level. Our findings indicate that somatic MECP2 mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline MECP2 mosaicism indicates an underestimated mechanism underlying the paternal origin bias of MECP2 variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin.
Males With MECP2 C-terminal-Related Atypical Rett Syndromes and Their Carrier Mothers
2017, Pediatric Neurology
Citation Excerpt :
Male phenotypes of these gene mutations range from lethal congenital and neonatal encephalopathies2 to PPM-X syndrome (psychosis and parkinsonism),5 nonspecific intellectual impairment,6 and other atypical presentations with ill-defined regression.7 Only a minority of males resemble the classic female RTT.8-10 Recognition and classification of male syndrome(s) continue to challenge clinicians and researchers.
This communication examines the expanding phenotypes of the MECP2 C-terminal atypical Rett syndromes in males and their affected carrier mothers.
We describe three males with normal karyotypes who presented with congenital evolving complex neurodevelopmental encephalopathies with multifaceted symptomatology of hypotonia, epilepsy, ataxia, spasticity, movement disorders, behavioral issues, severe intellectual impairment, and communication skills, and a protracted regression phase followed by stabilization. These phenotypes did not prompt us to identify atypical Rett syndrome early in childhood.
Genetic analysis identified the two brothers with C-terminal truncation and the third male with C-terminal missense mutations. These mutations were inherited from their mothers, both of whom had incompletely characterized modest intellectual, mental health, social, and gastrointestinal impairments. Neither was independently able to care properly for their son(s).
Mutations of the MECP2 gene should be considered early in males with hypotonia, developmental delay, profound intellectual impairment, and seizures, associated with a mother with psychosocial, cognitive, and gastrointestinal impairments. Counseling and supporting mildly affected mothers requires both medical and social efforts.
Rett Syndrome: Clinical Aspects
2016, Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability
Rett syndrome (RTT) affects 1:10,000 females, causing psychomotor regression and stereotypical hand movements. In the past half century, many clinical, neurobiological, and genetic aspects of RTT have been clarified, including identification of methyl CpG binding protein 2 gene mutations in most. Although loss of language and hand function and problems with ambulation are core disabilities in the disorder, a host of comorbidities affect girls and women with RTT. A Rett specialist typically works closely with other medical professionals, including therapists, nutritionists, social workers, and medical consultants related to the various systems affected. Most girls have problems that require the help of a neurologist or epileptologist, a gastroenterologist, and an orthopedic surgeon, and many require endocrinology and cardiology consultation. Within the past few years, an explosion in the investigation of disease-specific treatments has occurred, and targeted drugs will soon be available to help girls and women with RTT.

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Research LettersSomatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males

Summary

Am J Hum Genet

Rett Syndrome

J Med Genet

Research Letters
Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males