TY - JOUR
T1 - Diagnostic value of partial exome sequencing in developmental disorders
AU - Gieldon, Laura
AU - Mackenroth, Luisa
AU - Kahlert, Anne Karin
AU - Lemke, Johannes R.
AU - Porrmann, Joseph
AU - Schallner, Jens
AU - von der Hagen, Maja
AU - Markus, Susanne
AU - Weidensee, Sabine
AU - Novotna, Barbara
AU - Soerensen, Charlotte
AU - Klink, Barbara
AU - Wagner, Johannes
AU - Tzschach, Andreas
AU - Jahn, Arne
AU - Kuhlee, Franziska
AU - Hackmann, Karl
AU - Schrock, Evelin
AU - Di Donato, Nataliya
AU - Rump, Andreas
N1 - Publisher Copyright:
© 2018 Gieldon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/8
Y1 - 2018/8
N2 - Although intellectual disability is one of the major indications for genetic counselling, there are no homogenous diagnostic algorithms for molecular testing. While whole exome sequencing is increasingly applied, we questioned whether analyzing a partial exome, enriched for genes associated with Mendelian disorders, might be a valid alternative approach that yields similar detection rates but requires less sequencing capacities. Within this context 106 patients with different intellectual disability forms were analyzed for mutations in 4.813 genes after pre-exclusion of copy number variations by array-CGH. Subsequent variant interpretation was performed in accordance with the ACMG guidelines. By this, a molecular diagnosis was established in 34% of cases and candidate mutations were identified in additional 24% of patients. Detection rates of causative mutations were above 30%, regardless of further symptoms, except for patients with seizures (23%). We did not detect an advantage from partial exome sequencing for patients with severe intellectual disability (36%) as compared to those with mild intellectual disability (44%). Specific clinical diagnoses pre-existed for 20 patients. Of these, 5 could be confirmed and an additional 6 cases could be solved, but showed mutations in other genes than initially suspected. In conclusion partial exome sequencing solved >30% of intellectual disability cases, which is similar to published rates obtained by whole exome sequencing. The approach therefore proved to be a valid alternative to whole exome sequencing for molecular diagnostics in this cohort. The method proved equally suitable for both syndromic and non-syndromic intellectual disability forms of all severity grades.
AB - Although intellectual disability is one of the major indications for genetic counselling, there are no homogenous diagnostic algorithms for molecular testing. While whole exome sequencing is increasingly applied, we questioned whether analyzing a partial exome, enriched for genes associated with Mendelian disorders, might be a valid alternative approach that yields similar detection rates but requires less sequencing capacities. Within this context 106 patients with different intellectual disability forms were analyzed for mutations in 4.813 genes after pre-exclusion of copy number variations by array-CGH. Subsequent variant interpretation was performed in accordance with the ACMG guidelines. By this, a molecular diagnosis was established in 34% of cases and candidate mutations were identified in additional 24% of patients. Detection rates of causative mutations were above 30%, regardless of further symptoms, except for patients with seizures (23%). We did not detect an advantage from partial exome sequencing for patients with severe intellectual disability (36%) as compared to those with mild intellectual disability (44%). Specific clinical diagnoses pre-existed for 20 patients. Of these, 5 could be confirmed and an additional 6 cases could be solved, but showed mutations in other genes than initially suspected. In conclusion partial exome sequencing solved >30% of intellectual disability cases, which is similar to published rates obtained by whole exome sequencing. The approach therefore proved to be a valid alternative to whole exome sequencing for molecular diagnostics in this cohort. The method proved equally suitable for both syndromic and non-syndromic intellectual disability forms of all severity grades.
UR - http://www.scopus.com/inward/record.url?scp=85052295266&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0201041
DO - 10.1371/journal.pone.0201041
M3 - Article
C2 - 30091983
AN - SCOPUS:85052295266
SN - 1932-6203
VL - 13
JO - PLoS ONE
JF - PLoS ONE
IS - 8
M1 - e0201041
ER -