PURPOSE: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. METHODS: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. RESULTS: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. CONCLUSION: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

• Klíčová slova
• BIS, Nicolaides–Baraitser syndrome, SMARCA2, intellectual disability, neurodevelopmental disorder,
• MeSH
• blefarofimóza * MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• hypotrichóza * MeSH
• lidé MeSH
• mentální retardace * genetika   MeSH
• transkripční faktory genetika   MeSH
• vrozené deformity nohy (od hlezna dolů) MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• SMARCA2 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

BACKGROUND: Mutations in FOXL2 are known to cause autosomal dominant blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), variably associated with premature ovarian failure. In this study, we report results of mutational screening in a Czech and Slovak patient population with BPES. DESIGN: Case series. PARTICIPANTS: Thirteen probands of Czech and one proband of Slovak origin with BPES and their available family members. METHODS: Sanger sequencing and multiplex ligation-dependent probe amplification in 14 probands with BPES. Targeted mutational screening in first-degree relatives. MAIN OUTCOME MEASURES: Genetic characterization and phenotype evaluation in Czech and Slovak individuals with BPES and their family members. RESULTS: Eight different mutations were detected including three novel ones: c.5T>G; p.(Met2Arg), c.197C>A; p.(Ala66Glu) and c.701_702insTGCAGCCGCAGCGGCTGCAGCAGCTGCGGCTGCAGCCGC; p.(Ala222_Ala234dup). In one family, the molecular genetic cause of disease was not identified by the methodology used. In 13 pedigrees, a negative family history suggested a de novo origin, which could be confirmed by targeted mutational screening in four families. One 62-year-old female with the c.663_692dup30 mutation had an atypical phenotype presenting as moderate ptosis compensated by frontalis muscle contraction, no epicanthus inversus and no premature ovarian failure. CONCLUSIONS: The de novo mutation rate in FOXL2 is exceptionally high compared with other dominant disorders manifesting with an ocular phenotype. In cases reporting a negative family history, careful examination of both parents is important to exclude mild features of the BPES phenotype.

• Klíčová slova
• FOXL2, blepharophimosis-ptosis-epicanthus inversus syndrome, phenotype,
• MeSH
• blefarofimóza genetika   MeSH
• dítě MeSH
• DNA sondy MeSH
• dospělí MeSH
• fenotyp MeSH
• forkhead transkripční faktory genetika   MeSH
• genetické asociační studie MeSH
• kojenec MeSH
• kožní abnormality genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• missense mutace * MeSH
• mladiství MeSH
• multiplexová polymerázová řetězová reakce MeSH
• mutační analýza DNA MeSH
• předškolní dítě MeSH
• protein FOXL2 MeSH
• urogenitální abnormality genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA sondy MeSH
• forkhead transkripční faktory MeSH
• FOXL2 protein, human MeSH Prohlížeč
• protein FOXL2 MeSH

PURPOSE: To report the ocular phenotype of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). METHODS: Ophthalmological examination of a 36 year-old proband and detailed family history evaluation, including assessment of available facial photographs of affected relatives, was performed. RESULTS: There were four affected males and one female in three generations. The proband underwent two surgical eyelid procedures in childhood. Upon our examination, he had symmetrical ptosis with shorter eye lids, and incomplete medial canthal closure. The skin in the inner canthi was scarred, and the medial lower lids slightly everted, leading to malapposition of lacrimal punctae. There was no epicanthus inversus, however it was impossible to determine the status prior to the eyelid surgeries. The best corrected visual acuity was 0.66 and 0.33, in the right and left eye, respectively. The rest of the ocular examination was normal. There was no strabismus. Based on inspection of photographs taken prior to eyelid surgeries, the typical signs of BPES were also present in a son and a nephew of the proband. Photographs of the affected brother were not available, but family history indicated that he had BPES and underwent in his childhood two eye lid surgeries. Atypical ocular phenotype of the probands mother has been published previously. CONCLUSIONS: Ophthalmologists need to be aware about the phenotype of BPES, with the potential for visual impairment, and the need for personalized management in the affected families.Key words: blepharophimosis-ptosis-epicanthus inversus, phenotype, FOXL2.

• MeSH
• blefarofimóza diagnóza   genetika   chirurgie   MeSH
• blefaroplastika MeSH
• dospělí MeSH
• fenotyp MeSH
• kožní abnormality diagnóza   genetika   chirurgie   MeSH
• lidé MeSH
• oční víčka chirurgie   MeSH
• poruchy zraku diagnóza   genetika   chirurgie   MeSH
• rodokmen MeSH
• syndrom MeSH
• urogenitální abnormality diagnóza   genetika   chirurgie   MeSH
• zraková ostrost fyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) are two distinct clinically overlapping syndromes caused by de novo heterozygous truncating mutations in the KAT6B gene encoding lysine acetyltransferase 6B, a part of the histone H3 acetyltransferase complex. We describe an 8-year-old girl with a KAT6B mutation and a combined GPS/SBBYSS phenotype. The comparison of this patient with 61 previously published cases with KAT6B mutations and GPS, SBBYSS or combined GPS/SBBYSS phenotypes allowed us to separate the KAT6B mutations into four groups according to their position in the gene (reflecting nonsense mediated RNA decay and protein domains) and their clinical outcome. We suggest that mutations in mid-exon 18 corresponding to the C-terminal end of the acidic (Asp/Glu-rich) domain of KAT6B may have more variable expressivity leading to GPS, SBBYSS or combined phenotypes, in contrast to defects in other regions of the gene which contribute more specifically to either GPS or SBBYSS. Notwithstanding the clinical overlap, our cluster analysis of phenotypes of all known patients with KAT6B mutations supports the existence of two clinical entities, GPS and SBBYSS, as poles within the KAT6B-related disease spectrum. The awareness of these phenomena is important for qualified genetic counselling of patients with KAT6B mutations.

• Klíčová slova
• Genitopatellar syndrome, Genotype-phenotype correlation, KAT6B, Say-Barber-Biesecker-Young-Simpson syndrome,
• MeSH
• blefarofimóza diagnóza   genetika   MeSH
• dítě MeSH
• exony * MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• histonacetyltransferasy genetika   MeSH
• kongenitální hypotyreóza diagnóza   genetika   MeSH
• kraniofaciální abnormality diagnóza   genetika   MeSH
• ledviny abnormality   MeSH
• lidé MeSH
• mentální retardace diagnóza   genetika   MeSH
• molekulární sekvence - údaje MeSH
• mutace * MeSH
• nestabilita kloubu diagnóza   genetika   MeSH
• patela abnormality   MeSH
• psychomotorické poruchy diagnóza   genetika   MeSH
• sekvence nukleotidů MeSH
• skrotum abnormality   MeSH
• urogenitální abnormality diagnóza   genetika   MeSH
• vrozené srdeční vady diagnóza   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histonacetyltransferasy MeSH
• KAT6B protein, human MeSH Prohlížeč