TY - JOUR
T1 - Clinical genetics can solve the pitfalls of genome-wide investigations: Lesson from mismapping a loss-of-function variant in KANSL1
AU - Bigoni, Stefania
AU - Marangi, Giuseppe
AU - Frangella, Silvia
AU - Panfili, Arianna
AU - Ognibene, Davide
AU - Squeo, Gabriella Maria
AU - Merla, Giuseppe
AU - Zollino, Marcella
PY - 2020
Y1 - 2020
N2 - Massive parallel sequencing of 70 genes in a girl with a suspicion of chromatinopathy detected the (NM_015443.4:)c.985_986delTT variant in exon 2 of KANSL1, which led to a diagnostic consideration of Koolen De Vries syndrome. The same variant was present in the healthy mother, consistent with either incomplete penetrance or variant mismapping. A network of second opinion was implemented among clinical geneticists first, and a diagnosis of Koolen De Vries syndrome was considered unlikely. By MLPA, a duplication spanning exons 1-3 of KANSL1 was detected in both the mother and the daughter. On cDNA sequencing, biallelic wild type mRNA was observed. We concluded that the variant affects the noncoding duplicated gene region in our family, and we finally classified it as benign. Parallel wide genomic sequencing is increasingly the first genetic investigation in individuals with intellectual disability. The c.985_986delTT variant in KANSL1 was described both in individuals with typical KdVS and in a limited number of healthy subjects. This report highlights the role of clinical genetics to correctly classify variants and to define proper clinical and diagnostic correlations.
AB - Massive parallel sequencing of 70 genes in a girl with a suspicion of chromatinopathy detected the (NM_015443.4:)c.985_986delTT variant in exon 2 of KANSL1, which led to a diagnostic consideration of Koolen De Vries syndrome. The same variant was present in the healthy mother, consistent with either incomplete penetrance or variant mismapping. A network of second opinion was implemented among clinical geneticists first, and a diagnosis of Koolen De Vries syndrome was considered unlikely. By MLPA, a duplication spanning exons 1-3 of KANSL1 was detected in both the mother and the daughter. On cDNA sequencing, biallelic wild type mRNA was observed. We concluded that the variant affects the noncoding duplicated gene region in our family, and we finally classified it as benign. Parallel wide genomic sequencing is increasingly the first genetic investigation in individuals with intellectual disability. The c.985_986delTT variant in KANSL1 was described both in individuals with typical KdVS and in a limited number of healthy subjects. This report highlights the role of clinical genetics to correctly classify variants and to define proper clinical and diagnostic correlations.
KW - Clinical evaluation
KW - Copy number polymorphisms
KW - KANSL1
KW - Variant interpretation
KW - Clinical evaluation
KW - Copy number polymorphisms
KW - KANSL1
KW - Variant interpretation
UR - http://hdl.handle.net/10807/179366
U2 - 10.3390/genes11101177
DO - 10.3390/genes11101177
M3 - Article
SN - 2073-4425
VL - 11
SP - 1
EP - 6
JO - Genes
JF - Genes
ER -