An infant withMLH3variants,FOXG1-duplication and multiple, benign cranial and spinal tumors: A clinical exome sequencing study
| Autor: | Samuel P. Strom, Naghmeh Dorrani, Jean Reiss, Hane Lee, Peter Shintaku, Andrew Y. Shuen, Christopher E. Pearson, Fred H. Laningham, Eric Vilain, Joseph J. Shen, Gagan B. Panigrahi, Sibel Kantarci, David Samuel, Xinmin Li, Rina Kansal, Joshua L. Deignan, Wayne W. Grody |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Sanger sequencing congenital hereditary and neonatal diseases and abnormalities Cancer Research Microsatellite instability Biology medicine.disease Bioinformatics 03 medical and health sciences symbols.namesake 030104 developmental biology MSH2 Gene duplication Genetics symbols medicine PMS2 Neurofibromatosis Exome Exome sequencing |
| Zdroj: | Genes, Chromosomes and Cancer. 55:131-142 |
| ISSN: | 1045-2257 |
| Popis: | A 4-month-old male infant presented with severe developmental delay, cerebellar, brainstem, and cutaneous hemangiomas, bilateral tumors (vestibular, hypoglossal, cervical, and lumbar spinal), and few cafe-au-lait macules. Cerebellar and lumbar tumor biopsies revealed venous telangiectasia and intraneural perineuroma, respectively. Sequencing NF1, NF2, and RASA1 (blood), and NF2 and SMARCB1 (lumbar biopsy) was negative for pathogenic mutations. Clinical exome sequencing (CES), requested for tumor syndrome diagnosis, revealed two heterozygous missense variants, c.359T>C;p.Phe120Ser and c.3344G>A;p.Arg1115Gln, in MLH3 (NM_001040108.1), a DNA mismatch repair (MMR) gene, Polyphen-predicted as probably damaging, and benign, respectively. Sanger sequencing confirmed both variants in the proband, and their absence in the mother; biological father unavailable. Both biopsied tissues were negative for microsatellite instability, and expressed MLH1, MSH2, PMS2, MSH6, and MLH3 immunohistochemically. Chromosomal microarray showed a 133 kb segment copy number duplication of 14q12 region encompassing FOXG1, possibly explaining the developmental delay, but not the tumors. The presence of MLH3 variants with multiple benign neural and vascular tumors was intriguing for their possible role in the pathogenesis of these neoplasms, which were suspicious for, but not diagnostic of, constitutional MMR deficiency. However, functional assays of non-neoplastic patient-derived cells showed intact base-base MMR function. Also, no previous FOXG1-aberrant patient was reported with tumors. We now report a 3-year-old FOXG1-duplicated patient with a yet undescribed tumor syndrome with clinical features of neurofibromatosis types I and II, where several validation studies could not ascertain the significance of CES findings; further studies may elucidate precise mechanisms and diagnosis for clinical management, including tumor surveillance. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text