Abstract Details

Title Recurrent mosaic MTOR c.5930C>T (p.Thr1977Ile) Variant Causing Megalencephaly, Asymmetric Polymicrogyria, and Cutaneous Pigmentary Mosaicism

Topic Child Neurology and Developmental Neurology

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 7-037

Objective

To describe a case of de novo mosaic c.5930C>T (p.Thr1977Ile) MTOR variant presenting with megalencephaly, obstructive hydrocephalus, polymicrogyria, dysgenesis of the corpus callosum, hypotonia, developmental delay, and cutaneous pigmentary mosaicism, for which genetic diagnosis was made through analysis of fibroblasts derived from hyperpigmented skin patch, while testing of peripheral blood failed to yield detect any abnormalities in MTOR or other genes associated with brain overgrowth syndromes.

Background Genetic alterations leading to overactivation of mammalian target of rapamycin (mTOR) signaling have been linked to brain overgrowth syndromes such as focal cortical dysplasia (FCD) and megalencephaly. Megalencephaly with cutis tri-color of the Blaschko-linear type pigmentary mosaicism and intellectual disability is a rare neurodevelopmental disorder attributed to the recurrent mosaic c.5930C>T (p.Thr1977Ile) variant in MTOR. This variant was previously reported at low to intermediate levels of mosaicism in the peripheral blood of three unrelated individuals with consistent clinical findings.

Design/Methods NA

Results We report a fourth case of a 3-year-old female presenting with megalencephaly, obstructive hydrocephalus due to cerebral aqueductal stenosis, asymmetric polymicrogyria, dysgenesis of the corpus callosum, hypotonia, developmental delay, and cutaneous pigmentary mosaicism. Oligonucleotide and SNP chromosomal microarray (CMA), karyotype, and trio whole exome sequencing (WES) in the peripheral blood, as well as targeted gene panel from fibroblasts derived from hyperpigmented and non-hyperpigmented skin did not detect any abnormalities in MTOR or other genes associated with brain overgrowth syndromes. However, WES in fibroblasts derived from hyperpigmented skin detected a de novo c.5930C>T (p.Thr1977Ile) MTOR variant at 32% mosaicism, consistent with previously published variant in patients with similar clinical features to our patient.

Conclusions

Our case further expands the understanding of the phenotypic spectrum associated with the mosaic MTOR c.5930C>T (p.Thr1977Ile) variant and highlights the importance of genetic investigations in multiple tissues or cell types when a somatic neurodevelopmental disorder is suspected.

Authors/Disclosures
Maureen Handoko-Yang, MD (Rocky Mountain Neurodiagnostics) PRESENTER	Dr. Handoko has nothing to disclose.
Lisa T. Emrick, MD (Department of Neurology & Developmental Neuroscience)	Dr. Emrick has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Arkema. The institution of Dr. Emrick has received research support from Lysogene. The institution of Dr. Emrick has received research support from PTC. The institution of Dr. Emrick has received research support from Roche. The institution of Dr. Emrick has received research support from NIH.
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Hsiao-Tuan Chao, MD (Jan and Dan Duncan Neurological Research Institute)	An immediate family member of Dr. Chao has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Capsida. An immediate family member of Dr. Chao has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for COMBINEDBrain. Dr. Chao has received research support from NIH, Burroughs Wellcome Fund, the Pediatric Epilepsy Research Foundation, Cain Foundation for Epilepsy Research, the Robert and Janice McNair Foundation, and Texas Children's Hospital. An immediate family member of Dr. Chao has received intellectual property interests from a discovery or technology relating to health care.

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