TY - JOUR
T1 - The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA)study
AU - Luirink, Ilse K.
AU - Braamskamp, Marjet J. A. M.
AU - Wiegman, Albert
AU - Hartgers, Merel L.
AU - Sjouke, Barbara
AU - Defesche, Joep C.
AU - Hovingh, G. Kees
PY - 2019
Y1 - 2019
N2 - Background: Homozygous familial hypercholesterolemia (hoFH)is either diagnosed on the identification of pathogenic genetic variants in LDLR, APOB, or PCSK9 or by phenotypic parameters of which an extremely elevated LDL-C level >13 mmol/L (>500 mg/dL)is the most prominent hallmark. Little is known about the clinical spectrum in children with hoFH. Objective: We set out to investigate the phenotypical spectrum of genetically defined hoFH in our pediatric cohort and evaluated how many pediatric patients, now classified as heterozygous, carry a second mutation, which would reclassify these patients as hoFH. Methods: We analyzed the data of a total of 1903 children with molecularly proven FH. Subsequently we performed candidate gene sequencing in the cohort of heterozygous familial hypercholesterolemia children in whom the LDL-C level was above the lowest level measured in the pediatric patients with hoFH. Results: Of our 13 hoFH children, 8 (62%)had LDL-C levels below the clinical hoFH criteria of 13 mmol/L (500 mg/dL). In the remaining 1890 patients with heterozygous familial hypercholesterolemia, 64 (3.4%)had LDL-C levels equal to or above the lowest LDL-C level in a patient with hoFH carrying 2 deleterious variants (8.36 mmol/L or 323.3 mg/dL). No additional pathogenic variants in LDLR and APOB were identified. In 2 related patients, a PCSK9 gain of function mutation was found. Conclusion: We show that LDL-C levels vary among pediatric patients with molecularly proven hoFH, and that most of these patients do not meet the clinical LDL-C criteria for hoFH. The levels overlap with LDL-C levels in true heterozygous patients. This warrants a critical reappraisal of the current LDL-C cutoffs for the phenotypic diagnosis of hoFH in children.
AB - Background: Homozygous familial hypercholesterolemia (hoFH)is either diagnosed on the identification of pathogenic genetic variants in LDLR, APOB, or PCSK9 or by phenotypic parameters of which an extremely elevated LDL-C level >13 mmol/L (>500 mg/dL)is the most prominent hallmark. Little is known about the clinical spectrum in children with hoFH. Objective: We set out to investigate the phenotypical spectrum of genetically defined hoFH in our pediatric cohort and evaluated how many pediatric patients, now classified as heterozygous, carry a second mutation, which would reclassify these patients as hoFH. Methods: We analyzed the data of a total of 1903 children with molecularly proven FH. Subsequently we performed candidate gene sequencing in the cohort of heterozygous familial hypercholesterolemia children in whom the LDL-C level was above the lowest level measured in the pediatric patients with hoFH. Results: Of our 13 hoFH children, 8 (62%)had LDL-C levels below the clinical hoFH criteria of 13 mmol/L (500 mg/dL). In the remaining 1890 patients with heterozygous familial hypercholesterolemia, 64 (3.4%)had LDL-C levels equal to or above the lowest LDL-C level in a patient with hoFH carrying 2 deleterious variants (8.36 mmol/L or 323.3 mg/dL). No additional pathogenic variants in LDLR and APOB were identified. In 2 related patients, a PCSK9 gain of function mutation was found. Conclusion: We show that LDL-C levels vary among pediatric patients with molecularly proven hoFH, and that most of these patients do not meet the clinical LDL-C criteria for hoFH. The levels overlap with LDL-C levels in true heterozygous patients. This warrants a critical reappraisal of the current LDL-C cutoffs for the phenotypic diagnosis of hoFH in children.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85061652557&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30795984
U2 - https://doi.org/10.1016/j.jacl.2018.12.003
DO - https://doi.org/10.1016/j.jacl.2018.12.003
M3 - Article
C2 - 30795984
SN - 1933-2874
VL - 13
SP - 272
EP - 278
JO - Journal of clinical lipidology
JF - Journal of clinical lipidology
IS - 2
ER -