Identification of a founder effect involving n.197C>T variant in RMRP gene associated to cartilage-hair hypoplasia syndrome in Brazilian patients.

Cartilage-hair hypoplasia syndrome (CHH) is an autosomal recessive disorder frequently linked to n.72A>G (previously known as n.70A>G and n.71A>G), the most common RMRP variant worldwide. More than 130 pathogenic variants in this gene have already been described associated with CHH, and founder alterations were reported in the Finnish and Japanese populations. Our previous study in Brazilian CHH patients showed a high prevalence of n.197C>T variant (former n.195C>T and n.196C>T) when compared to other populations. The aim of this study was to investigate a possible founder effect of the n.197C>T variant in the RMRP gene in a series of CHH Brazilian patients. We have selected four TAG SNPs within chromosome 9 and genotyped the probands and their parents (23 patients previously described and nine novel). A common haplotype to the n.197C>T variant carriers was identified. Patients were also characterized for 46 autosomal Ancestry Informative Markers (AIMs). European ancestry was the most prevalent (58%), followed by African (24%) and Native American (18%). Our results strengthen the hypothesis of a founder effect for the n.197C>T variant in Brazil and indicate that this variant in the RMRP gene originated from a single event on chromosome 9 with a possible European origin.

10q23.31 microduplication encompassing PTEN decreases mTOR signalling activity and is associated with autosomal dominant primary microcephaly.

BACKGROUND: Hereditary primary microcephaly (MCPH) is mainly characterised by decreased occipitofrontal circumference and variable degree of intellectual disability. MCPH with a dominant pattern of inheritance is a rare condition, so far causally linked to pathogenic variants in the ALFY, DPP6, KIF11 and DYRK1A genes. OBJECTIVE: This study aimed at identifying the causative variant of the autosomal dominant form of MCPH in a Brazilian family with three affected members. METHODS: Following clinical evaluation of two sibs and their mother presenting with autosomal dominant MCPH, array comparative genome hybridisation was performed using genomic DNA from peripheral blood of the family members. Gene and protein expression studies were carried out in cultured skin fibroblasts. RESULTS: A 382 kb microduplication at 10q23.31 was detected, encompassing the entire PTEN, KLLN and ATAD1 genes. PTEN haploinsufficiency has been causally associated with macrocephaly and autism spectrum disorder and, therefore, was considered the most likely candidate gene to be involved in this autosomal dominant form of MCPH. In the patients' fibroblasts, PTEN mRNA and protein were found to be overexpressed, and the phosphorylation patterns of upstream and downstream components of the mammalian target of rapamycin (mTOR) signalling pathway were dysregulated. CONCLUSIONS: Taken together, our results demonstrate that the identified submicroscopic 10q23.31 duplication in a family with MCPH leads to markedly increased expression of PTEN and reduced activity of the mTOR signalling pathway. These results suggest that the most probable pathomechanism underlying the microcephaly phenotype in this family involves downregulation of the mTOR pathway through overexpression of PTEN.

Expanding the Clinical Spectrum of Phenotypes Caused by Pathogenic Variants in PLOD2.

Osteogenesis imperfecta (OI) is a strikingly heterogeneous group of disorders with a broad range of phenotypic variations. It is also one of the differential diagnoses in bent bone dysplasias along with campomelic dysplasia and thanatophoric dysplasia and can usually be distinguished by decreased bone mineralization and bone fractures. Bent bone dysplasias also include syndromes such as kyphomelic dysplasia (MIM:211350) and mesomelic dysplasia Kozlowski-Reardon (MIM249710), both of which have been under debate regarding whether or not they are a real entity or simply a phenotypic manifestation of another dysplasia including OI. Bruck syndrome type 2 (BRKS2; MIM:609220) is a rare form of autosomal recessive OI caused by biallelic PLOD2 variants and is associated with congenital joint contractures with pterygia. In this report, we present six patients from four families with novel PLOD2 variants. All cases had multiple fractures. Other features ranged from prenatal lethal severe angulation of the long bones as in kyphomelic dysplasia and mesomelic dysplasia Kozlowski-Reardon through classical Bruck syndrome to moderate OI with normal joints. Two siblings with a kyphomelic dysplasia-like phenotype who were stillborn had compound heterozygous variants in PLOD2 (p.Asp585Val and p.Ser166*). One infant who succumbed at age 4 months had a bent bone phenotype phenotypically like skeletal dysplasia Kozlowski-Reardon (with mesomelic shortening, camptodactyly, retrognathia, cleft palate, skin dimples, but also with fractures). He was homozygous for the nonsense variant (p.Trp561*). Two siblings had various degrees of Bruck syndrome caused by the homozygous missense variant, p.His687Arg. Furthermore a boy with a clinical presentation of moderate OI had a possibly pathogenic homozygous variant p.Trp588Cys. Our experience of six patients with biallelic pathogenic variants in PLOD2 expands the phenotypic spectrum in the PLOD2-related phenotypes. © 2017 American Society for Bone and Mineral Research.

Y chromosome in Turner syndrome: detection of hidden mosaicism and the report of a rare X;Y translocation case.

Turner syndrome (TS) is a common genetic disorder in females associated with the absence of complete or parts of a second sex chromosome. In 5-12% of patients, mosaicism for a cell line with a normal or structurally abnormal Y chromosome is identified. The presence of Y-chromosome material is of medical importance because it results in an increased risk of developing gonadal tumours and virilisation. Molecular study and fluorescence in situ hybridisation approaches were used to study 74 Brazilian TS patients in order to determine the frequency of hidden Y-chromosome mosaicism, and to infer the potential risk of developing malignancies. Additionally, we describe one TS girl with a very uncommon karyotype 46,X,der(X)t(X;Y)(p22.3?2;q11.23) comprising a partial monosomy of Xp22.3?2 together with a partial monosomy of Yq11.23. The presence of cryptic Y-chromosome-specific sequences was detected in 2.7% of the cases. All patients with Y-chromosome-positive sequences showed normal female genitalia with no signs of virilisation. Indeed, the clinical data from Y-chromosome-positive patients was very similar to those with Y-negative results. Therefore, we recommend that the search for hidden Y-chromosome mosaicism should be carried out in all TS cases and not be limited to virilised patients or carriers of a specific karyotype.

Implementing the brazilian database on orofacial clefts.

Background. High-quality clinical and genetic descriptions are crucial to improve knowledge of orofacial clefts and support specific healthcare polices. The objective of this study is to discuss the potential and perspectives of the Brazilian Database on Orofacial Clefts. Methods. From 2008 to 2010, clinical and familial information on 370 subjects was collected by geneticists in eight different services. Data was centrally processed using an international system for case classification and coding. Results. Cleft lip with cleft palate amounted to 198 (53.5%), cleft palate to 99 (26.8%), and cleft lip to 73 (19.7%) cases. Parental consanguinity was present in 5.7% and familial history of cleft was present in 26.3% subjects. Rate of associated major plus minor defects was 48% and syndromic cases amounted to 25% of the samples. Conclusions. Overall results corroborate the literature. Adopted tools are user friendly and could be incorporated into routine patient care. The BDOC exemplifies a network for clinical and genetic research. The data may be useful to develop and improve personalized treatment, family planning, and healthcare policies. This experience should be of interest for geneticists, laboratory-based researchers, and clinicians entrusted with OC worldwide.