Identification of copy number variants associated with BPES-like phenotypes

Gijsbers, Antoinet C.J.; D’haene, Barbara; Hilhorst‐Hofstee, Yvonne; Mannens, Marcel M.A.M.; Albrecht, Beate; Seidel, Joerg; Witt, David R.; Maisenbacher, Melissa; Loeys, Bart; Essen, Ton van; Bakker, Egbert; Hennekam, Raoul C. M.; Breuning, Martijn H.; Baere, Elfride De; Ruivenkamp, Claudia

doi:10.1007/s00439-008-0574-9

Cited by 14 publications

(5 citation statements)

References 22 publications

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“…Microdeletions encompassing a larger genomic region around FOXL2 were found in individuals referred to as BPES plus, who in addition to BPES have additional features, such as developmental delay, speech delay, and genital anomaly [Costa et al, ; D'haene et al, ; Zahanova et al, ]. Further, a subset of BPES plus individuals (33%) was found to have other pathogenic CNVs not affecting FOXL2 [Gijsbers et al, ; D'haene et al, ].…”

Section: Introductionmentioning

confidence: 99%

An individual with blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B

Geiger

Medne

et al. 2014

American J of Med Genetics Pt A

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Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) is an autosomal dominant disorder caused by mutations in FOXL2. We identified an individual with BPES and additional phenotypic features who did not have a FOXL2 mutation. We used whole exome sequencing to identify a de novo mutation in KAT6B (lysine acetyltransferase 6B) in this individual. The mutation was a 2 bp insertion leading to a frameshift which resulted in a premature stop codon. The resulting truncated protein does not have the C-terminal serine/methionine transcription activation domain necessary for interaction with other transcriptional and epigenetic regulators. This mutation likely has a dominant-negative or gain-of-function effect, similar to those observed in other genetic disorders resulting from KAT6B mutations, including Say-Barber-Biesecker-Young-Simpson (SBBYSS) and Genitopatellar syndrome (GTPTS). Thus, our subject’s phenotype broadens the spectrum of clinical findings associated with mutations in KAT6B. Furthermore, our results suggest that individuals with BPES without a FOXL2 mutation should be tested for KAT6B mutations. The transcriptional and epigenetic regulation mediated by KAT6B appears crucial to early developmental processes, which when perturbed can lead to a wide spectrum of phenotypic outcomes.

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Section: Introductionmentioning

confidence: 99%

An individual with blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B

Geiger

Medne

et al. 2014

American J of Med Genetics Pt A

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“…using quantitative polymerase chain reaction [qPCR] or microarray-based comparative genome hybridisation [array CGH]) is recommended as a third step to exclude the presence of regulatory copy number changes affecting the long-range genetic control of FOXL2 which have been reported in 4% of the cases [27,30]. In case of a BPES-like phenotype, genome-wide microarray-based copy number screening is recommended, as copy number changes can be detected in a relatively large proportion of these patients (33%) [33]. …”

Section: Guidelines For Molecular Genetic Testing Of Bpesmentioning

confidence: 99%

<i>FOXL2 </i>Impairment in Human Disease

Verdin¹,

Baere²

2012

Horm Res Paediatr

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FOXL2 encodes a forkhead transcription factor that plays important roles in the ovary during development and in post-natal, adult life. Here, we focus on the clinical consequences of FOXL2 impairment in human disease. In line with other forkhead transcription factors, its constitutional genetic defects and a somatic mutation lead to developmental disease and cancer, respectively. More than 100 unique constitutional mutations and regulatory defects have been found in blepharophimosis syndrome (BPES), a complex eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). In agreement with the BPES phenotype, FOXL2 is expressed in the developing eyelids and in fetal and adult ovaries. Two knock-out mice and at least one natural animal model, the Polled Intersex Syndrome goat, are known. They recapitulate the BPES phenotype and have provided many insights into the ovarian pathology. Only a few constitutional mutations have been described in nonsyndromic POF. Moreover, a recurrent somatic mutation p.C134W was found to be specific for adult ovarian granulo-sa cell tumors. Functional studies investigating the consequences of FOXL2 mutations or regulatory defects have shed light on the molecular pathogenesis of the aforementioned conditions, and contributed considerably to genotype-phenotype correlations. Recently, a conditional knock-out of Foxl2 in the mouse induced somatic transdifferentiation of ovary into testis in adult mice, suggesting that Foxl2 has an anti-testis function in the adult ovary. This changed our view on the ovary and testis as terminally differentiated organs in adult mammals. Finally, this might have potential implications for the understanding and treatment of frequent conditions such as POF and polycystic ovary syndrome.

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“…From a clinical standpoint, we suggest that ADNP mutations should be considered in the differential diagnosis of blepharophimosis syndrome. The majority of patients with blepharophimosis, ptosis, and epicanthus inversus syndrome have mutations in FOXL2 (Crisponi et al, ), and copy number variations are observed in one‐third of patients who do not have mutations in FOXL2 (Gijsbers et al, ). ADNP mutation screening is warranted in patients with blepharophimosis syndrome who do not have a mutation in FOXL2 , or copy number variations involving FOXL2 .…”

Section: Discussionmentioning

confidence: 99%

Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene

Tamura

Miwa

Sakamoto

et al. 2017

American J of Med Genetics Pt A

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Heterozygous truncating mutations in ADNP are associated with a syndromic form of intellectual disability known as Helsmoortel-van der Aa syndrome. Among 17 previously reported patients with Helsmoortel-van der Aa syndrome, one patient exhibited blepharophimosis. Whether blepharophimosis represents a phenotypic expression of the ADNP mutation spectrum or a chance association remains unclear. Herein, we report another patient with a de novo truncating mutation in ADNP who exhibited a combination of blepharophimosis and epicanthal folds. In our retrospective re-evaluation of six originally reported patients whose facial photographs were available, at least one patient indeed had blepharophimosis and epicanthal folds. Furthermore, all three patients with blepharophimosis and epicanthal folds, including the presently reported patient, had truncating mutations at the same specific portion of the protein, that is the bipartite nuclear localization signal. We suggest that this specific class of ADNP mutation is likely associated with a blepharophimosis syndrome phenotype. From a clinical standpoint, a differential diagnosis of patients with blepharophimosis should include ADNP mutations in addition to blepharophimosis ptosis epicanthus inversus syndrome, especially when intellectual disability is present.

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Identification of copy number variants associated with BPES-like phenotypes

Cited by 14 publications

References 22 publications

An individual with blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B

An individual with blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B

<i>FOXL2 </i>Impairment in Human Disease

Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene

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