Two new Rett syndrome families and review of the literature: expanding the knowledge of MECP2 frameshift mutations

<p>Abstract</p> <p>Background</p> <p>Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder, which is usually caused by <it>de novo </it>mutations in the <it>MECP2 </it>gene. More than 70% of the disease causing <it>MECP2 </it>mutations are eight recurrent C to T transitions, which almost exclusively arise on the paternally derived X chromosome. About 10% of the RTT cases have a C-terminal frameshift deletion in <it>MECP2</it>. Only few RTT families with a segregating <it>MECP2 </it>mutation, which affects female carriers with a phenotype of mental retardation or RTT, have been reported in the literature. In this study we describe two new RTT families with three and four individuals, respectively, and review the literature comparing the type of mutations and phenotypes observed in RTT families with those observed in sporadic cases. Based on these observations we also investigated origin of mutation segregation to further improve genetic counselling.</p> <p>Methods</p> <p><it>MECP2 </it>mutations were identified by direct sequencing. XCI studies were performed using the X-linked androgen receptor (<it>AR</it>) locus. The parental origin of <it>de novo MECP2 </it>frameshift mutations was investigated using intronic SNPs.</p> <p>Results</p> <p>In both families a C-terminal frameshift mutation segregates. Clinical features of the mutation carriers vary from classical RTT to mild mental retardation. XCI profiles of the female carriers correlate to their respective geno-/phenotypes. The majority of the <it>de novo </it>frameshift mutations occur on the paternally derived X chromosome (7/9 cases), without a paternal age effect.</p> <p>Conclusions</p> <p>The present study suggests a correlation between the intrafamilial phenotypic differences observed in RTT families and their respective XCI pattern in blood, in contrast to sporadic RTT cases where a similar correlation has not been demonstrated. Furthermore, we found <it>de novo MECP2 </it>frameshift mutations frequently to be of paternal origin, although not with the same high paternal occurrence as in sporadic cases with C to T transitions. This suggests further investigations of more families. This study emphasizes the need for thorough genetic counselling of families with a newly diagnosed RTT patient.</p

Apolipoprotein ɛ4 Status and Brain Structure 12 Months after Mild Traumatic Injury: Brain Age Prediction Using Brain Morphometry and Diffusion Tensor Imaging

Background: Apolipoprotein E (APOE) ɛ4 is associated with poor outcome following moderate to severe traumatic brain injury (TBI). There is a lack of studies investigating the influence of APOE ɛ4 on intracranial pathology following mild traumatic brain injury (MTBI). This study explores the association between APOE ɛ4 and MRI measures of brain age prediction, brain morphometry, and diffusion tensor imaging (DTI). Methods: Patients aged 16 to 65 with acute MTBI admitted to the trauma center were included. Multimodal MRI was performed 12 months after injury and associated with APOE ɛ4 status. Corrections for multiple comparisons were done using false discovery rate (FDR). Results: Of included patients, 123 patients had available APOE, volumetric, and DTI data of sufficient quality. There were no differences between APOE ɛ4 carriers (39%) and non-carriers in demographic and clinical data. Age prediction revealed high accuracy both for the DTI-based and the brain morphometry based model. Group comparisons revealed no significant differences in brain-age gap between ɛ4 carriers and non-carriers, and no significant differences in conventional measures of brain morphometry and volumes. Compared to non-carriers, APOE ɛ4 carriers showed lower fractional anisotropy (FA) in the hippocampal part of the cingulum bundle, which did not remain significant after FDR adjustment. Conclusion: APOE ɛ4 carriers might be vulnerable to reduced neuronal integrity in the cingulum. Larger cohort studies are warranted to replicate this finding

Mapping of the Locus for Cholestasis-Lymphedema Syndrome (Aagenaes Syndrome) to a 6.6-cM Interval on Chromosome 15q

Patients with cholestasis-lymphedema syndrome (CLS) suffer severe neonatal cholestasis that usually lessens during early childhood and becomes episodic; they also develop chronic severe lymphedema. The genetic cause of CLS is unknown. We performed a genome screen, using DNA from eight Norwegian patients with CLS and from seven unaffected relatives, all from an extended pedigree. Regions potentially shared identical by descent in patients were further characterized in a larger set of Norwegian patients. The patients manifest extensive allele and haplotype sharing over the 6.6-cM D15S979–D15S652 region: 30 (83.3%) of 36 chromosomes of affected individuals carry a six-marker haplotype not found on any of the 32 nontransmitted parental chromosomes. All Norwegian patients with CLS are likely homozygous for the same disease mutation, inherited from a shared ancestor

CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops.

Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS.Consanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes.Both siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known 'cholestasis genes' did not demonstrate homozygosity in the LCS patient.Mutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded

Regions of homozygosity shared by the two affected siblings.

<p>The genotyping information is displayed as a B-allele frequency, with heterozygous SNPs plotted at 0.5, and homozygous plotted at 0 or 1. B-allele frequencies are shown for chromosome 13 (A) and 18 (B). For each chromosome, B-allele frequencies are shown for Patient 1 (top) and Patient 2 (bottom).</p