BACKGROUND: Axenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition. METHODS: Genetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses. RESULTS: 128 individuals with causative variants in PITX2 or FOXC1, including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1-related ARS. Systemic anomalies were seen in all individuals with PITX2-related ARS and the majority of those with FOXC1-related ARS. PITX2-related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1-related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1-related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS. CONCLUSION: Since clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.

• Klíčová slova
• congenital, hereditary, and neonatal diseases and abnormalities, eye diseases, genetics, genetics, medical,
• MeSH
• abnormality očí * genetika   diagnóza   MeSH
• forkhead transkripční faktory genetika   MeSH
• homeodoménové proteiny * genetika   MeSH
• lidé MeSH
• mutace MeSH
• přední segment oční abnormality   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• forkhead transkripční faktory MeSH
• homeodoménové proteiny * MeSH
• transkripční faktory MeSH

• MeSH
• Downův syndrom * MeSH
• gynekologie * MeSH
• krk MeSH
• lidé MeSH
• měření nuchální translucence MeSH
• porodnictví * MeSH
• první trimestr těhotenství MeSH
• řízení kvality MeSH
• těhotenství MeSH
• ultrasonografie prenatální MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH

OBJECTIVE: The establishment of ongoing audits for first-trimester nuchal translucency (NT) measurements is of paramount importance. The exponentially weighted moving average (EWMA) chart has been published as an efficient tool for NT quality control with the advantages of being suitable for real-time long-term monitoring. This study aimed to assess the efficacy of real-time NT quality control using EWMA charts. MATERIALS AND METHODS: This was an ongoing prospective study conducted from January 2011 to December 2017 at the Centre for Fetal Medicine Gennet in Prague. The quality of NT measurements was assessed using the NT retrospective distribution parameters and EWMA charts, and the results were presented to the sonographers during collective meetings. RESULTS: Overall, 28,928 NT measurements obtained from six sonographers were eligible for the study. Looking at individual EWMA charts, we observed four main outcomes. First, there was a clear improvement in the performance of sonographers with initially poor performances. Second, the performance of sonographers with an initially satisfactory quality was maintained. Third, there was an observed deterioration of the performance without the audits. Last, the sonographers appreciated an unequivocal and straightforward graphical presentation of EWMA curves. CONCLUSION: EWMA proved to be an efficient and suitable tool for real-time monitoring of NT quality and led to an overall improvement of the sonographers' performance.

• Klíčová slova
• Exponentially weighted moving average chart, First trimester, Nuchal translucency, Statistical quality control, Ultrasound,
• MeSH
• interpretace statistických dat MeSH
• lidé MeSH
• měření nuchální translucence normy   MeSH
• prospektivní studie MeSH
• první trimestr těhotenství MeSH
• referenční standardy MeSH
• retrospektivní studie MeSH
• řízení kvality * MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

We observed bilateral cataracts on second trimester ultrasound, in two consecutive pregnancies, with no other structural defects detected. The parents were unrelated and had no family history for the disease. The first pregnancy was terminated in week 22. Copy number variation analysis revealed, in both the aborted fetus and the mother, a 495 kb duplication at 22q11.23 encompassing CRYBB3 and CRYBB2, and not present in variation databases. In the second pregnancy, lens hyperechogenicity was detected by ultrasound at week 13 and 4 days. The identical duplication at 22q11.23 was found in the fetus and considered as possibly pathogenic. At weeks 22 and 30, smaller orbit measurements were elucidated on ultrasound, raising concerns as to the underlying molecular genetic cause, necessitating further investigation. Whole-exome sequencing, using DNA of the first fetus, was performed shortly after the birth of a male child, and two truncating RAB3GAP1 mutations were detected: c.538G>T; p. (Glu180*) and c.943C>T; p. (Arg315*). Neither mutation has been previously reported to be disease-causing; however, evaluation in the context of previously published literature indicated their deleterious nature, implying a clinical diagnosis of Warburg micro syndrome or Martsolf syndrome. Sanger sequencing confirmed segregation of the two mutations within the family, consistent with autosomal recessive inheritance. The child born from the second pregnancy showed features typical of Warburg micro syndrome, with the exception of microcephaly, at age 31 months. © 2016 Wiley Periodicals, Inc.

• Klíčová slova
• CRYBB2, CRYBB3, DNA copy number variations, RAB3GAP1, Warburg micro syndrome, high-throughput nucleotide sequencing, prenatal ultrasonography,
• MeSH
• atrofie optického nervu diagnóza   genetika   patofyziologie   MeSH
• beta-krystaliny - řetězec B genetika   MeSH
• exony genetika   MeSH
• hypogonadismus diagnóza   genetika   patofyziologie   MeSH
• katarakta vrozené   diagnóza   genetika   patofyziologie   MeSH
• kojenec MeSH
• lidé MeSH
• mentální retardace diagnóza   genetika   patofyziologie   MeSH
• mikrocefalie diagnóza   genetika   patofyziologie   MeSH
• mnohočetné abnormality diagnóza   genetika   patofyziologie   MeSH
• mutace MeSH
• novorozenec MeSH
• potracený plod patofyziologie   MeSH
• Rab3 proteiny vázající GTP genetika   MeSH
• rodokmen MeSH
• rohovka abnormality   patofyziologie   MeSH
• sekvenční analýza DNA MeSH
• těhotenství MeSH
• ultrasonografie prenatální MeSH
• variabilita počtu kopií segmentů DNA genetika   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• beta-crystallin B2 MeSH Prohlížeč
• beta-krystaliny - řetězec B MeSH
• CRYBB3 protein, human MeSH Prohlížeč
• Rab3 proteiny vázající GTP MeSH
• RAB3GAP1 protein, human MeSH Prohlížeč

A substantial proportion of patients with posterior polymorphous corneal dystrophy (PPCD) lack a molecular diagnosis. We evaluated 14 unrelated probands who had a clinical diagnosis of PPCD who were previously determined to be negative for mutations in ZEB1 by direct sequencing. A combination of techniques was used including whole-exome sequencing (WES), single-nucleotide polymorphism (SNP) array copy number variation (CNV) analysis, quantitative real-time PCR, and long-range PCR. Segregation of potentially pathogenic changes with disease was confirmed, where possible, in family members. A putative run of homozygosity on chromosome 10 was identified by WES in a three-generation PPCD family, suggestive of a heterozygous deletion. SNP array genotyping followed by long-range PCR and direct sequencing to define the breakpoints confirmed the presence of a large deletion that encompassed multiple genes, including ZEB1. Identification of a heterozygous deletion spanning ZEB1 prompted us to further investigate potential CNVs at this locus in the remaining probands, leading to detection of two additional heterozygous ZEB1 gene deletions. This study demonstrates that ZEB1 mutations account for a larger proportion of PPCD than previously estimated, and supports the hypothesis that haploinsufficiency of ZEB1 is the underlying molecular mechanism of disease for PPCD3.

• MeSH
• dědičné dystrofie rohovky genetika   patologie   MeSH
• delece genu * MeSH
• dítě MeSH
• dospělí MeSH
• haploinsuficience * MeSH
• heterozygot MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• rodokmen MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktor Zeb1 genetika   MeSH
• variabilita počtu kopií segmentů DNA MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• transkripční faktor Zeb1 MeSH
• ZEB1 protein, human MeSH Prohlížeč