Clinical intrafamilial variability in lethal familial neonatal seizure disorder caused by TBC1D24 mutations.

TBC1D24-related disorders include a wide phenotypic ranging from mild to lethal seizure disorders, non-syndromic deafness, and composite syndromes such as DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). The TBC1D24 gene has a role in cerebral cortex development and in presynaptic neurotransmission. Here, we present a familial case of a lethal early-onset epileptic encephalopathy, associated with two novel compound heterozygous missense variants on the TBC1D24 gene, which were detected by exome sequencing. The detailed clinical data of the three siblings is summarized in order to support the variability of the phenotype, severity, and progression of this disorder among these family members. Functional studies demonstrated that the identified novel missense mutations result in a loss of expression of the protein, suggesting a correlation between residual expression, and the disease severity. This indicates that protein expression analysis is important for interpreting genetic results when novel variants are found, as well as for complementing clinical assessment by predicting the functional impact. Further analysis is necessary to delineate the clinical presentation of individuals with TBC1D24 pathogenic variants, as well as to develop markers for diagnosis, prognosis, and potential targeted treatments. © 2016 Wiley Periodicals, Inc.

Familial 4p Interstitial Deletion Provides New Insights and Candidate Genes Underlying This Rare Condition.

Chromosome 4p deletions can lead to two distinct phenotypic outcomes: Wolf--Hirschhorn syndrome (a terminal deletion at 4p16.3) and less frequently reported proximal interstitial deletions (4p11-p16). Proximal 4p interstitial deletions can result in mild to moderate intellectual disability, facial dysmorphisms, and a tall thin body habitus. To date, only 35 cases of proximal 4p interstitial deletions have been reported, and only two of these cases have been familial. The critical region for this syndrome has been narrowed down to 4p15.33-15.2, but the underlying causative genes remain unclear. In this study, we report the case of a 3-year-old female with failure to thrive, developmental and motor delays, and morphological features. The mother also had a 4p15.2-p14 deletion, and the proband was found to have a 13.4-Mb 4p15.2-p14 deletion by chromosome microarray analysis. The deleted region encompasses 16 genes, five of which have a high likelihood of contributing to the phenotype: PPARGC1A, DHX15, RBPJ, STIM2, and PCDH7. These findings suggest that multiple genes are involved in this rare proximal 4p interstitial deletion syndrome. This case highlights the need for healthcare providers to be aware of proximal 4p interstitial deletions and the potential phenotypic manifestations.

Language ENvironment Analysis (LENA) in Phelan-McDermid Syndrome: Validity and Suggestions for Use in Minimally Verbal Children with Autism Spectrum Disorder.

Phelan-McDermid syndrome (PMS) is a single-locus cause of developmental delay, autism spectrum disorder, and minimal verbal abilities. There is an urgent need to identify objective outcome measures of expressive language for use in this and other minimally verbal populations. One potential tool is an automated language processor called Language ENvironment Analysis (LENA). LENA was used to obtain over 542 h of audio in 18 children with PMS. LENA performance was adequate in a subset of children with PMS, specifically younger children and those with fewer stereotypic vocalizations. One LENA-derived language measure, Vocalization Ratio, had improved accuracy in this sample and may represent a novel expressive language measure for use in severely affected populations.