Whole exome sequencing identifies multiple diagnoses in congenital glaucoma with systemic anomalies.
The genetic basis of congenital glaucoma with systemic anomalies is largely unknown. Whole exome sequencing (WES) in 10 probands with congenital glaucoma and variable systemic anomalies identified pathogenic or likely pathogenic variants in three probands; in two of these, a combination of two Mendelian disorders was found to completely explain the patients' features whereas in the third case only the ocular findings could be explained by the genetic diagnosis. The molecular diagnosis for glaucoma included two cases with compound heterozygous or homozygous pathogenic alleles in CYP1B1 and one family with a dominant pathogenic variant in FOXC1; the second genetic diagnosis for the additional systemic features included compound heterozygous mutations in NPHS1 in one family and a heterozygous 18q23 deletion in another pedigree. These findings show the power of WES in the analysis of complex conditions and emphasize the importance of CYP1B1 screening in patients with congenital glaucoma regardless of the presence/absence of other systemic anomalies.
Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA.
L M
LM
Reis
Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA.
R C
RC
Tyler
Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA.|Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
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E
Weh
Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA.|Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
K E
KE
Hendee
Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA.|Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
K F
KF
Schilter
Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
J A
JA
Phillips
Metabolic Unit, Pediatric Department, Hospital de Dona Estefânia, CHLC, Lisbon, Portugal.
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S
Sequeira
Department of Genetics, Institute of Medical Genetics, Schwerzenbach, Switzerland.
A
A
Schinzel
Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA. esemina@mcw.edu.|Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA. esemina@mcw.edu.|Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI, USA. esemina@mcw.edu.
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Semina
D000483:Alleles; D065633:Cytochrome P-450 CYP1B1 / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics; D005901:Glaucoma / Q000151:congenital / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D010375:Pedigree; D017422:Sequence Analysis, DNA
C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; C113267:nephrin; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1
18q23 deletion; CYP1B1; FOXC1; NPHS1; congenital glaucoma; exome sequencing; multiple diagnoses