Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Boonsawat Paranchai, Joset Pascal, Steindl Katharina, Oneda Beatrice, Gogoll Laura, Azzarello-Burri Silvia, Sheth Frenny, Datar Chaitanya, Verma Ishwar C, Puri Ratna Dua, Zollino Marcella, Bachmann-Gagescu Ruxandra, Niedrist Dunja, Papik Michael, Figueiro-Silva Joana, Masood Rahim, Zweier Markus, Kraemer Dennis, Lincoln Sharyn, Rodan Lance, Undiagnosed Diseases Network (UDN), Passemard Sandrine, Drunat Séverine, Verloes Alain, Horn Anselm H C, Sticht Heinrich, Steinfeld Robert, Plecko Barbara, Latal Beatrice, Jenni Oskar, Asadollahi Reza, Rauch Anita
Аннотация
METHODS: We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset).
RESULTS: We found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for ~5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDX1).
CONCLUSION: Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.