Shifting the landscape: Dominant C-terminal rare missense FOXL2 variants in non-syndromic primary ovarian failure etiology.

Pathogenic germline variants in the FOXL2 gene are associated with Blepharophimosis, Ptosis, and Epicanthus Inversus syndrome (BPES) in humans, an autosomal dominant condition. Two forms of BPES have emerged: (i) type I (BPES-I), characterized by ocular signs and primary ovarian failure (POI), and (ii) type II (BPES-II) with no systemic associations. This study aimed to compare the distribution of FOXL2 variants in idiopathic POI/DOR (diminished ovarian reserve) and both types of BPES, and to determine the involvement of FOXL2 in non-syndromic forms of POI/DOR. We studied the whole coding region of the FOXL2 gene using next-generation sequencing in 1282 patients with non-syndromic POI/DOR. Each identified FOXL2 variant was compared to its frequency in the general population, considering ethnicity. Screening of the entire coding region of the FOXL2 gene allowed us to identify 10 different variants, including nine missense variants. Of the patients with POI/DOR, 14 (1%) carried a FOXL2 variant. Significantly, six out of nine missense variants (67%) were overrepresented in our POI/DOR cohort compared to the general or specific ethnic subgroups. Our findings strongly suggest that five rare missense variants, mainly located in the C-terminal region of FOXL2 are high-risk factors for non-syndromic POI/DOR, though FOXL2 gene implication accounts for approximately 0.54% of non-syndromic POI/DOR cases. These results support the implementation of routine genetic screening for patients with POI/DOR in clinical settings.

Qualitative and quantitative analysis of MED12 c.887G>A causing both missense and splicing variants in X-linked Ohdo syndrome.

The phenotypes associated with MED12 pathogenic variants are diverse. Male patients usually have missense variants, but the effects of base substitutions on mRNA splicing have not been investigated. Here, we report a Japanese brother with intellectual disability, characteristic facial appearance with blepharophimosis, cleft palate, Fallot tetralogy, vesicoureteral reflux, and deafness. A known missense pathogenic variant was detected in MED12, NM_005120.3:c.887G>A p.(Arg296Gln), and X-linked Ohdo syndrome was diagnosed in combination with their phenotype. mRNA splicing of MED12 was evaluated qualitatively and quantitatively using long-range PCR-based targeted RNA sequencing (reverse transcribed long amplicon sequencing), and it was shown that this missense variant simultaneously causes aberrant splicing of the 42-bp in-frame deletion in exon 7, r.847_888del, which accounts for approximately 30% of the mRNAs in both siblings. The X chromosome inactivation study showed that the X chromosome carrying the mutant allele was 100% inactivated in the carrier mothers. mRNA level analysis is essential for the accurate interpretation of the effects of variants. In this case, the MED12 protein function may be reduced by more than just an amino acid substitution, resulting in the patients with the most severe phenotype of MED12-related syndrome in males.

De novo KAT6B mutation causes Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome in an Iranian boy: a case report.

BACKGROUND: Say-Barber-Biesecker-Young-Simpson (SBBYS) (OMIM #603736, Ohdo syndrome variant) is a rare type of severe blepharophimosis intellectual disability syndrome, which is generally characterized by a global developmental delay, distinctive facial features, and intellectual disability with multiple congenital anomalies, including skeletal involvement, missing, or underdeveloped kneecaps, and genital anomalies, in affected males. It has been shown that mutations in the KAT6B gene, which is a lysine acetyltransferase-encoding gene, have been associated with SBBYS syndrome. All the known variants are dominant de novo mutations that result in protein truncation. CASE PRESENTATION: A 14-year-old Iranian Azeri boy with an intellectual disability, distinct dysmorphic facial features such as open-mouth expression, sparse medial eyebrows, widely spaced upward-slanted eyes, epicanthal folds, broad nasal bridge, low-set ears, anteverted ears, short philtrum, hypertelorism, microphthalmia is presented in this case study. Cryptorchidism was reported. Neurologically, the patient presented with poor eye contact, hypotonia, and speech difficulties. In the skeletal X-ray, underdeveloped kneecaps with some new features were observed. CONCLUSION: We present the first case of SBBYS syndrome in association with some new anomaly features in the Iranian population. Based on this diagnosis, we could provide the patient with a suitable plan of management as well as appropriate genetic counseling for his family.

Estudos moleculares em anomalias craniofaciais raras: sindrome blefaroqueilodontica e efeitos de linha media facial com hipertelorismo / Molecular biological studies in rare craniofacial anomalies

A Síndrome Blefaroqueilodôntica (BCD) e os Defeitos de Linha Média Facial com Hipertelorismo (DLMFH) são defeitos craniofaciais raros. Por esse motivo, os estudos de grandes casuísticas têm sido limitados. Contribuição científica significativa neste assunto tem sido dada por nosso grupo, que delineou características clínicas e diretrizes para seguimento de longo prazo e evidenciou achados neuroradiológicos em ambas as anomalias. Embasado nesses achados preliminares e evidências recentes da literatura pertinente, foi possível estabelecer uma estratégia inicial para investigação etiológica da BCD e dos DLMFH, sendo os objetivos desse projeto: investigar a etiologia da BCD nos indivíduos afetados pela síndrome, por meio de estudo dos genes candidatos IRF6, P63, OSR2, TBX10, FOXE1, SHH, FGF8 e PAX3; pesquisar, nos indivíduos com DLMFH, a presença de mutações nos genes candidatos SHH, FGF8 e PAX3; identificar, em ambas as malformações, possíveis alterações cromossômicas; e, por último, associar os achados clínicos detectados nas investigações anteriores aos possíveis achados moleculares. Foram utilizadas técnicas de sequenciamento direto, array-CGH, genotipagem automática e hibridação in situ por fluorescência. Não foi possível relacionar nenhuma mutação pontual nos genes estudados associadas às malformações em questão, pois não foram encontradas alterações gênicas patogênicas. Entretanto foram detectadas em pacientes com DLFMH três aberrações cromossômicas em regiões distintas do genoma, tratando-se de um caso de duplicação no cromossomo...

The Blepharocheilodontic Syndrome (BCD) and Midline Facial Defects with Ocular Hypertelorism (MFDH) are rare craniofacial anomalies. Considering the rarity of these two groups of congenital defects, studies with large casuistry have been limited. Our group has significantly contributed to the scientific knowledge about both anomalies, delineating clinical characteristics, evidencing neurological findings and designing protocols for long term follow-up. Based in these preliminary findings and recent evidences of pertinent literature, it was possible to determine an initial etiologic investigation strategy for the BCD and the MFDH. The objectives of this project are to investigate the etiology of the BCD in affected individuals through IRF6, P63, OSR2, TBX10, FOXE1, SHH, FGF8 and PAX3 candidate genes study; to search MFDH patients for mutations in the SHH, FGF8 and PAX3 candidate genes; to identify, in both syndromes...