Variants in Candidate Genes for Phenotype Heterogeneity in Patients with the 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving ∼3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variants that could act as genetic modifiers and contribute to the phenotypic heterogeneity, using a targeted NGS (Next Generation Sequencing) with a specific Ion AmpliSeq panel to sequence nine candidate genes (CRKL, MAPK1, HIRA, TANGO2, PI4KA, HDAC1, ZDHHC8, ZFPM2, and JAM3), mapped in and outside the 22q11.2 hemizygous deleted region. In silico prediction was performed, and the whole-genome sequencing annotation analysis package (WGSA) was used to predict the possible pathogenic effect of single nucleotide variants (SNVs). For the in silico prediction of the indels, we used the genomic variants filtered by a deep learning model in NGS (GARFIELD-NGS). We identified six variants, 4 SNVs and 2 indels, in MAPK1, JAM3, and ZFPM2 genes with possibly synergistic deleterious effects in the context of the 22q11.2 deletion. Our results provide the opportunity for the discovery of the co-occurrence of genetic variants with 22q11.2 deletions, which may influence the patients´ phenotype.

Morquio-like dysostosis multiplex presenting with neuronopathic features is a distinct GLB1-related phenotype.

BACKGROUND: Morquio B disease (MBD) is a distinct GLB1-related dysostosis multiplex presenting a mild phenocopy of GALNS-related Morquio A disease. Previously reported cases from European countries carry the W273L variant on at least one GLB1 allele and exhibit a pure skeletal phenotype (pure MBD). Only a minority of MBD cases have been described with additional neuronopathic findings (MBD plus). OBJECTIVES AND METHODS: With the aim to further describe patterns of MBD-related dysostosis multiplex, we analyzed clinical, biochemical, and genetic features in 17 cases with GLB1-related dysostosis multiplex living and diagnosed in Brazil. RESULTS: About 14 of the 17 individuals had three or more skeletal findings characteristic of Morquio syndrome. Two had no additional neuronopathic features (pure MBD) and 12 exhibited additional neuronopathic features (MBD plus). Three of the 17 cases had mild dysostosis without distinct features of MBD. Seven of the 12 MBD plus patients had signs of spinal cord compression (SCC), as a result of progressive spinal vertebral dysostosis. There was an age-dependent increase in the number of skeletal findings and in the severity of growth impairment. GLB1 mutation analysis was completed in 10 of the 14 MBD patients. T500A occurred in compound heterozygosity in 8 of the 19 alleles. CONCLUSION: Our study extends the phenotypic spectrum of GLB1-related conditions by describing a cohort of patients with MBD and GM1-gangliosidosis (MBD plus). Targeting the progressive nature of the skeletal manifestations in the development of new therapies for GLB1-related conditions is warranted.

Genetic investigation of patients with tall stature.

CONTEXT: Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach. OBJECTIVE: To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder. DESIGN: Screening by karyotype (n = 42), chromosome microarray analyses (CMA) (n = 16), MS-MLPA (n = 2) targeted panel (n = 12) and whole-exome sequencing (n = 31). PATIENTS AND METHODS: We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups. MAIN OUTCOME MEASURES: Frequencies of pathogenic findings. RESULTS: We identified two patients with chromosomal abnormalities including SHOX trisomy by karyotype, one 9q22.3 microdeletion syndrome by CMA, two cases of Beckwith-Wiedemann syndrome by targeted MS-MLPA analysis and nine cases with heterozygous pathogenic or likely pathogenic genetic variants by multigene analysis techniques (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1, MC4R = 1). Three of 20 patients analyzed by WES had their diagnosis established. Only one non-syndromic patient had a definitive diagnosis. The sequential genetic assessment diagnosed 14 out of 42 (33.3%) tall patients. CONCLUSION: A systematic molecular approach of patients with tall stature was able to identify the etiology in 13 out of 30 (43.3%) syndromic and 1 out of 12 (8.3%) non-syndromic patients, contributing to the genetic counseling and avoiding unfavorable outcomes in the syndromic subgroup.

Clinical characterization of autosomal dominant and recessive variants of Robinow syndrome.

Robinow syndrome is a genetically heterogeneous condition characterized by mesomelic limb shortening associated with facial and genital anomalies that can be inherited in an autosomal dominant or recessive mode. We characterized these two variants clinically, with the aim of establishing clinical criteria to enhance the differential diagnosis between them or other similar conditions. The frequencies of clinical signs considered important for the discrimination of the dominant or recessive variants were estimated in a sample consisting of 38 patients personally examined by the authors and of 50 affected subjects from the literature. Using the presence of rib fusions as diagnostic of the recessive variant, and also based on the inheritance pattern in familial cases, we classified 37 patients as having the recessive form and other 51 as having the dominant form. The clinical signs present in more than 75% of patients with either form, and therefore the most important for the characterization of this syndrome were hypertelorism, nasal features (large nasal bridge, short upturned nose, and anteverted nares), midface hypoplasia, mesomelic limb shortening, brachydactyly, clinodactyly, micropenis, and short stature. Hemivertebrae and scoliosis were present in more than 75% of patients with the recessive form, but in less than 25% of patients with the dominant form. Umbilical hernia (32.3%) and supernumerary teeth (10.3%) were found exclusively in patients with the dominant form.

Alterações comportamentais na Síndrome de Noonan: dados preliminares brasileiros / Behavioral disturbances in Noonan Syndrome: Brazilian preliminary data

Diferente de outros países de Europa e América do Norte, no Brasil, estudos sobre o perfil comportamental de pacientes com síndrome de Noonan (SN) são inexistentes. O objetivo do estudo foi traçar o perfil de funcionamento comportamental de 10 participantes (quatro do sexo feminino e seis do sexo masculino, sendo 8 adultos e 2 crianças), com mutação do gene PTPN11, compatível com a SN. Para isso, foram utilizados o Inventário de Comportamentos de Crianças e Adolescentes de 6 a 18 anos (CBCL/ 6-18) e o Inventário de Auto-Avaliação para Adultos de 18 a 59 anos (ASR). Os principais resultados apontam que na Escala de Funcionamento Adaptativo todos os participantes encontram-se na faixa de normalidade. Na Escala das Síndromes, os participantes adultos situam-se na normalidade e as crianças apresentam problemas, na faixa clínica, referentes às sub-escalas ansiedade/depressão, queixas somáticas e comportamento agressivo. Na Escala orientada pelo DSM, 25% dos pacientes adultos encontram-se na faixa limítrofe e clínica, respectivamente, quanto a problemas típicos de personalidade evitativa e problemas de personalidade anti-social e, ambas as crianças apresentaram escores dentro da faixa clínica nas sub-escalas problemas afetivos e problemas de ansiedade. Esta amostra que é relativamente homogênea em função do mesmo tipo de gene envolvido (PTPN11) mostrou um perfil comportamental médio, no caso dos adultos, dentro da normalidade. Entretanto, os perfis individuais, tanto dos participantes adultos como das crianças mostram diversos problemas de comportamento internalizantes e externalizantes.

Different from other countries of Europe and North American, studies about the behavioral profile of Noonan syndrome's patients are inexistent. The objective of this study was to report the profiles of behavioral functions of 10 participants (4 females and 6 males), with mutations in the PTPN11 gene. For this assessment it was used the Inventory of Behaviors of Children and Adolescents from 6 to 18 years (CBCL/6-18) and the Inventory of Auto-Evaluation for Adults from 18 to 59 years (ASR). The main results point that in Adaptive Functioning Scale all the participants were in the normality range. In the Syndrome Scale the adult participants were in normality range and the children were in clinical range to the sub-scales anxious/depressed, somatic complaints and aggressive behavior. In the DSM-Oriented Scale, 25% of the adult patients were in the borderline clinical range and clinical range, respectively, for Avoidant Personality Problems and Antisocial Personality Problems. About the both children in this scale were in the clinical range of Affective Problems and Anxiety Problems. This relatively homogenous sample, regarding the PTPN11 gene, shows a normal adult behavioral profile, on the average. However, the individual children and adult profiles show diverse internalizing and externalizing behavioral disturbances.