Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy

Topçu, Meral; Akyerli, Cemaliye Boylu; Sayi, A; Toruner, GA; Kocoglu,; Cimbis, M; Özçelık, Tayfun

doi:10.1038/sj.ejhg.5200745

Cited by 88 publications

(65 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On the most severe end is mosaicism for mutations presumably lethal in the non-mosaic state, as postulated for Proteus and macrocephaly-cutis marmorata telangiectatica congenita syndromes [Hamm, 1999]. Similarly, typically male lethal Xlinked disorders may be disease causing in mosaic males, as seen in classic Rett syndrome [Topcu et al, 2002]. Mosaicism for autosomal dominant disease causing mutations may cause segmental presentation of the typical findings, as in segmental neurofibromatosis type 1, a well-known entity due to the relatively high incidence and the easily identifiable skin findings.…”

Section: Discussionmentioning

confidence: 97%

Somatic mosaicism for an HRAS mutation causes Costello syndrome

Gripp

Stabley

Nicholson

et al. 2006

American J of Med Genetics Pt A

View full text Add to dashboard Cite

De novo heterozygous HRAS point mutations have been reported in more than 81 patients with Costello syndrome (CS), but genotype/phenotype correlation remains incomplete because the majority of patients share a common mutation, G12S, seen in 65/81 (80%). Somatic HRAS mutations have previously been identified in solid tumors, and mutation hot spots related to a gain-of-function effect of the gene product are known. The germline mutations causing CS occur at these hot spots and convey a gain-of-function effect, thus accounting for the greatly increased cancer risk. Diagnostic testing for HRAS mutations is now available and the identification of a mutation in a patient with consistent clinical findings confirms a diagnosis of CS. It is not clear yet if the absence of an HRAS mutation precludes a diagnosis of CS. Because there is a significant overlap in the clinical findings of Costello, cardio-facio-cutaneous, and Noonan syndromes, diagnostic uncertainty remains in patients lacking an HRAS mutation. We report here on a female with findings suggestive of CS in whom mutation analysis performed with standard techniques on white blood cell derived DNA did not show an HRAS mutation. However, analysis of DNA derived from three independently collected buccal swabs showed a sequence change qualitatively consistent with the G12S mutation. Allelic quantitation showed the presence of the mutation in approximately 25%-30% of the sampled buccal cells. In this patient, standard technology failed to identify the disease causing mutation on DNA derived from a blood sample, highlighting the potential pitfalls in the interpretation of negative mutation studies. This is the first reported CS patient mosaic for the common HRAS mutation, likely due to a somatic mutation occurring very early in fetal development.

show abstract

Section: Discussionmentioning

confidence: 97%

Somatic mosaicism for an HRAS mutation causes Costello syndrome

Gripp

Stabley

Nicholson

et al. 2006

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…in incontinentia pigmenti (IKBKG), Rett syndrome (MECP2), or chondrodysplasia punctata (EBP) (Metzenberg et al, 1999;Clayton-Smith et al, 2000;Armstrong et al, 2001;Kenwrick, 2001;Topçu et al, 2002). We assume that the paracentric inversion of the X chromosome occurred postzygotically in a particular subset of the patient's cells.…”

Section: Discussionmentioning

confidence: 99%

Microphthalmia with linear skin defects syndrome (MLS): a male with a mosaic paracentric inversion of Xp

Kutsche

Werner²,

Bartsch³

et al. 2002

Cytogenet Genome Res

View full text Add to dashboard Cite

The microphthalmia with linear skin defects syndrome (MLS) is an X-linked dominant disorder with male lethality. In the majority of the patients reported, the MLS syndrome is caused by segmental monosomy of the Xp22.3 region. To date, five male patients with MLS and 46,XX karyotype (“XX males”) have been described. Here we report on the first male case with MLS and an XY complement. The patient showed agenesis of the corpus callosum, histiocytoid cardiomyopathy, and lactic acidosis but no microphthalmia, and carried a mosaic subtle inversion of the short arm of the X chromosome in 15% of his peripheral blood lymphocytes, 46,Y,inv(X)(p22.13∼22.2p22.32∼22.33)[49]/46,XY[271]. By fluorescence in situ hybridization (FISH), we showed that YAC 225H10 spans the breakpoint in Xp22.3. End-sequencing and database analysis revealed a YAC insert of at least 416 kb containing the genes HCCS and AMELX, and exons 2–16 of ARHGAP6. Molecular cytogenetic data suggest that the Xp22.3 inversion breakpoint is located in intron 1 of ARHGAP6, the gene encoding the Rho GTPase activating protein 6. Future molecular studies in karyotypically normal female MLS patients to detect submicroscopic rearrangements including the ARHGAP6 gene as well as mutation screening of ARHGAP6 in patients with no obvious chromosomal rearrangements will clarify the role of this gene in MLS syndrome.

show abstract

“…7 Males with other mosaic MECP2 mutations have been reported as well. 18,19 Since they all exhibit features of classic RTT syndrome, it is suggested that an MECP2 mutation associated with RTT syndrome in females could lead to a similar phenotype in males as a result of somatic mosaicism. The clinical diagnosis of Rett syndrome was considered previously, but it was believed at that time that this syndrome did not occur in males.…”

Section: Discussionmentioning

confidence: 99%