TY - JOUR
T1 - Challenges in the clinical interpretation of small de novo copy number variants in neurodevelopmental disorders
AU - Magini, Pamela
AU - Scarano, Emanuela
AU - Donati, Ilaria
AU - Sensi, Alberto
AU - Mazzanti, Laura
AU - Perri, Annamaria
AU - Tamburrino, Federica
AU - Mongelli, Patrizia
AU - Percesepe, Antonio
AU - Visconti, Paola
AU - Parmeggiani, Antonia
AU - Seri, Marco
AU - Graziano, Claudio
N1 - Richiesto "CORRIGENDUM" per modifica di affiliazione (inserito nel pdf della pubblicazione qui allegato). .
PY - 2019/7/20
Y1 - 2019/7/20
N2 - In clinical genetics, the need to discriminate between benign and pathogenic variants identified in patients with neurodevelopmental disorders is an absolute necessity. Copy number variants (CNVs) of small size can enable the identification of genes that are critical for neurologic development. However, assigning a definite association with a specific disorder is a difficult task. Among 328 trios analyzed over seven years of activity in a single laboratory, we identified 19 unrelated patients (5.8%) who carried a small (<500 kb) de novo CNV. Four patients had an additional independent de novo CNV. Nine had a variant that could be assigned as definitely pathogenic, whereas the remaining CNVs were considered as variants of unknown significance (VUS). We report clinical and molecular findings of patients harboring VUS. We reviewed the medical literature available for genes impacted by CNVs, obtained the probability of truncating loss-of-function intolerance, and compared overlapping CNVs reported in databases. The classification of small non-recurrent CNVs remains difficult but, among our findings, we provide support for a role of SND1 in the susceptibility of autism, describe a new case of the rare 17p13.1 microduplication syndrome, and report an X-linked duplication involving KIF4A and DLG3 as a likely cause of epilepsy.
AB - In clinical genetics, the need to discriminate between benign and pathogenic variants identified in patients with neurodevelopmental disorders is an absolute necessity. Copy number variants (CNVs) of small size can enable the identification of genes that are critical for neurologic development. However, assigning a definite association with a specific disorder is a difficult task. Among 328 trios analyzed over seven years of activity in a single laboratory, we identified 19 unrelated patients (5.8%) who carried a small (<500 kb) de novo CNV. Four patients had an additional independent de novo CNV. Nine had a variant that could be assigned as definitely pathogenic, whereas the remaining CNVs were considered as variants of unknown significance (VUS). We report clinical and molecular findings of patients harboring VUS. We reviewed the medical literature available for genes impacted by CNVs, obtained the probability of truncating loss-of-function intolerance, and compared overlapping CNVs reported in databases. The classification of small non-recurrent CNVs remains difficult but, among our findings, we provide support for a role of SND1 in the susceptibility of autism, describe a new case of the rare 17p13.1 microduplication syndrome, and report an X-linked duplication involving KIF4A and DLG3 as a likely cause of epilepsy.
KW - 17p13.1 duplication
KW - Autism
KW - DNMT3A
KW - Intellectual disability
KW - SND1
KW - Xq13.1 duplication
UR - http://www.scopus.com/inward/record.url?scp=85065647984&partnerID=8YFLogxK
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U2 - 10.1016/j.gene.2019.05.007
DO - 10.1016/j.gene.2019.05.007
M3 - Article
C2 - 31085274
AN - SCOPUS:85065647984
VL - 706
SP - 162
EP - 171
JO - Gene
JF - Gene
SN - 0378-1119
ER -