TY - JOUR
T1 - Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly
AU - Undiagnosed Diseases Network (UDN)
AU - Boonsawat, Paranchai
AU - Joset, Pascal
AU - Steindl, Katharina
AU - Oneda, Beatrice
AU - Gogoll, Laura
AU - Azzarello-Burri, Silvia
AU - Sheth, Frenny
AU - Datar, Chaitanya
AU - Verma, Ishwar C
AU - Puri, Ratna Dua
AU - Zollino, Marcella
AU - Bachmann-Gagescu, Ruxandra
AU - Niedrist, Dunja
AU - Papik, Michael
AU - Figueiro-Silva, Joana
AU - Masood, Rahim
AU - Zweier, Markus
AU - Kraemer, Dennis
AU - Lincoln, Sharyn
AU - Rodan, Lance
AU - Passemard, Sandrine
AU - Drunat, Séverine
AU - Verloes, Alain
AU - Horn, Anselm H C
AU - Sticht, Heinrich
AU - Steinfeld, Robert
AU - Plecko, Barbara
AU - Latal, Beatrice
AU - Jenni, Oskar
AU - Asadollahi, Reza
AU - Rauch, Anita
PY - 2019/9
Y1 - 2019/9
N2 - PURPOSE: Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly.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.
AB - PURPOSE: Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly.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.
U2 - 10.1038/s41436-019-0464-7
DO - 10.1038/s41436-019-0464-7
M3 - Article
C2 - 30842647
SN - 1098-3600
VL - 21
SP - 2043
EP - 2058
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 9
ER -