RESUMEN
Low-pass whole genome sequencing (LP-WGS) has been applied as alternative method to detect copy number variants (CNVs) in the clinical setting. Compared with chromosomal microarray analysis (CMA), the sequencing-based approach provides a similar resolution of CNV detection at a lower cost. In this study, we assessed the efficiency and reliability of LP-WGS as a more affordable alternative to CMA. A total of 1363 patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies were enrolled. Those patients were referred from 15 nonprofit organizations and university centers located in different states in Brazil. The analysis of LP-WGS at 1x coverage (>50kb) revealed a positive testing result in 22% of the cases (304/1363), in which 219 and 85 correspond to pathogenic/likely pathogenic (P/LP) CNVs and variants of uncertain significance (VUS), respectively. The 16% (219/1363) diagnostic yield observed in our cohort is comparable to the 15%-20% reported for CMA in the literature. The use of commercial software, as demonstrated in this study, simplifies the implementation of the test in clinical settings. Particularly for countries like Brazil, where the cost of CMA presents a substantial barrier to most of the population, LP-WGS emerges as a cost-effective alternative for investigating copy number changes in cytogenetics.
Asunto(s)
Variaciones en el Número de Copia de ADN , Secuenciación Completa del Genoma , Humanos , Variaciones en el Número de Copia de ADN/genética , Secuenciación Completa del Genoma/economía , Secuenciación Completa del Genoma/métodos , Brasil , Masculino , Femenino , Niño , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Análisis Costo-Beneficio , Análisis por Micromatrices/economía , Análisis por Micromatrices/métodos , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/diagnóstico , Preescolar , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico , Países en Desarrollo , Adolescente , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , Pruebas Genéticas/economía , Pruebas Genéticas/métodosRESUMEN
Ramon syndrome (OMIM #266270) was first described in a patient with cherubism, gingival fibromatosis, epilepsy, intellectual disability, hypertrichosis, and stunted growth. In 2018, Mehawej et al. described a patient with Ramon syndrome in whom a homozygous variant in ELMO2 was identified, suggesting that this gene may be the causative for this syndrome. ELMO2 biallelic pathogenic variants were also described in patients with a primary intraosseous vascular malformation (PIVM; OMIM #606893). These patients presented gingival bleeding and cherubism phenotype. Herein, a patient with gingival hypertrophy, neurodevelopmental delay, and cherubism phenotype with a novel homozygous predicted loss-of-function (LOF) variant in the ELMO2 gene and family recurrence was reported. A surgical approach to treat gingival bleeding and mandible vascular malformation was also described. Furthermore, this study includes a comprehensive literature review of molecular data regarding the ELMO2 gene. All the variants, except one described in the ELMO2, were predicted as LOF, including our patient's variant. There is an overlapping between PIVM, also caused by LOF biallelic variants in the ELMO2 gene, and Ramon syndrome, which can suggest that they are not different entities. However, due to a limited number of cases described with molecular evaluation, it is hard to establish a genotype-phenotype correlation. Our study supports that LOF pathogenic biallelic variants in the ELMO2 gene cause a phenotype that has cherubism and gingival hypertrophy as main characteristics.
Asunto(s)
Alelos , Querubismo , Hipertrofia Gingival , Fenotipo , Humanos , Querubismo/genética , Querubismo/patología , Querubismo/diagnóstico , Hipertrofia Gingival/genética , Hipertrofia Gingival/patología , Masculino , Femenino , Fibromatosis Gingival/genética , Fibromatosis Gingival/patología , Fibromatosis Gingival/diagnóstico , Niño , Proteínas Adaptadoras Transductoras de Señales/genética , Homocigoto , Mutación/genéticaRESUMEN
BACKGROUND: Next-generation sequencing has had a significant impact on genetic disease diagnosis, but the interpretation of the vast amount of genomic data it generates can be challenging. To address this, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology have established guidelines for standardized variant interpretation. In this manuscript, we present the updated Hospital Israelita Albert Einstein Standards for Constitutional Sequence Variants Classification, incorporating modifications from leading genetics societies and the ClinGen initiative. RESULTS: First, we standardized the scientific publications, documents, and other reliable sources for this document to ensure an evidence-based approach. Next, we defined the databases that would provide variant information for the classification process, established the terminology for molecular findings, set standards for disease-gene associations, and determined the nomenclature for classification criteria. Subsequently, we defined the general rules for variant classification and the Bayesian statistical reasoning principles to enhance this process. We also defined bioinformatics standards for automated classification. Our workgroup adhered to gene-specific rules and workflows curated by the ClinGen Variant Curation Expert Panels whenever available. Additionally, a distinct set of specifications for criteria modulation was created for cancer genes, recognizing their unique characteristics. CONCLUSIONS: The development of an internal consensus and standards for constitutional sequence variant classification, specifically adapted to the Brazilian population, further contributes to the continuous refinement of variant classification practices. The aim of these efforts from the workgroup is to enhance the reliability and uniformity of variant classification.
Asunto(s)
Pruebas Genéticas , Variación Genética , Humanos , Estados Unidos , Mutación , Reproducibilidad de los Resultados , Teorema de Bayes , Genoma HumanoRESUMEN
We determined the frequency and mutational spectrum of BRCA1 and BRCA2 in a series of patients at high risk for developing breast cancer from Brazil. A total of 1267 patients were referred for BRCA genetic testing, and no obligation of fulfilling criteria of mutation probability methods for molecular screening was applied. Germline deleterious mutations in BRCA1/2 (i.e., pathogenic/likely pathogenic variants) were identified in 156 out of 1267 patients (12%). We confirm recurrent mutations in BRCA1/2, but we also report three novel mutations in BRCA2, not previously reported in any public databases or other studies. Variants of unknown significance (VUS) represent only 2% in this dataset and most of them were detected in BRCA2. The overall mutation prevalence in BRCA1/2 was higher in patients diagnosed with cancer at age > 35 years old, and with family history of cancer. The present data expand our knowledge of BRCA1/2 germline mutational spectrum, and it is a valuable clinical resource for genetic counseling and cancer management programs in the country.
Asunto(s)
Proteína BRCA1 , Proteína BRCA2 , Neoplasias de la Mama , Adulto , Femenino , Humanos , Brasil/epidemiología , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Mutación , Neoplasias Ováricas/genéticaRESUMEN
Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy-Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4-15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.
RESUMEN
Duplication of the distal 1q and 4p segments are both characterized by the presence of intellectual disability/neurodevelopmental delay and dysmorphisms. Here, we describe a male with a complex chromosome rearrangement (CCR) presenting with overlapping clinical findings between these 2 syndromes. In order to better characterize this CCR, classical karyotyping, FISH, and chromosomal microarray analysis were performed on material from the patient and his parents, which revealed an unbalanced karyotype with duplications at 1q41q43 and 4p15.2p14 in the proband. The rearrangements, which were derived from a maternal balanced karyotype, included an insertion of a segment from the long to the short arm of chromosome 1, a balanced translocation involving chromosomes 14 and 18, and an insertion of a segment from the short arm of chromosome 4 into the derived chromosome 14. This study aimed to better define the clinical history and prognosis of a patient with this rare category of chromosomal aberration. Our results suggest that the frequency of CCR in the general population may be underestimated; when balanced, they may not have a phenotypic effect. Moreover, they emphasize the need for cytogenetic techniques complementary to chromosomal microarray for proper genetic counseling.
RESUMEN
Chromosomal microarray analyses (CMA) have greatly increased both the yield and diagnostic accuracy of postnatal analysis; it has been used as a first-tier cytogenetic test in patients with intellectual disability, autism spectrum disorder, and multiple congenital abnormalities. During the last 15 years, we performed CMA in approximately 8,000 patients with neurodevelopmental and/or congenital disorders, of which 13 (0.16%) genetically catastrophic complex chromosomal rearrangements were identified. These ultrarare rearrangements showed clustering of breakpoints, characteristic of chromoanagenesis events. Al1 13 complex events display underlying formation mechanisms, originating either by a synchronization of the shattering of clustered chromosome regions in which regional asynchrony of DNA replication may be one of the main causes of disruption. We provide an overview of the copy number profiling in these patients. Although several previous studies have suggested that chromoanagenesis is often a genetic disease source in postnatal diagnostic screening, due to either the challenge of clinical interpretation of these complex rearrangements or the limitation of microarray resolution relative to the small size and complexity of chromogenic induced chromosome abnormalities, bringing further attention and to study its occurrence in the clinical setting is extremely important.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Aberraciones Cromosómicas , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Anomalías Múltiples/epidemiología , Adolescente , Adulto , Brasil/epidemiología , Niño , Preescolar , Trastornos de los Cromosomas/epidemiología , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/genética , Pruebas Diagnósticas de Rutina , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
We aim to characterize patients with Gomez-López-Hernández syndrome (GLHS) clinically and to investigate them molecularly. A clinical protocol, including a morphological and neuropsychological assessment, was applied to 13 patients with GLHS. Single-nucleotide polymorphism (SNP) array and whole-exome sequencing were undertaken; magnetic resonance imaging was performed in 12 patients, including high-resolution, heavily T2-weighted sequences (HRT2) in 6 patients to analyze the trigeminal nerves. All patients presented alopecia; two did not present rhombencephalosynapsis (RES); trigeminal anesthesia was present in 5 of the 11 patients (45.4%); brachycephaly/brachyturricephaly and mid-face retrusion were found in 84.6 and 92.3% of the patients, respectively. One patient had intellectual disability. HRT2 sequences showed trigeminal nerve hypoplasia in four of the six patients; all four had clinical signs of trigeminal anesthesia. No common candidate gene was found to explain GLHS phenotype. RES does not seem to be an obligatory finding in respect of GLHS diagnosis. We propose that a diagnosis of GLHS should be considered in patients with at least two of the following criteria: focal non-scarring alopecia, rhombencephalosynapsis, craniofacial anomalies (brachyturrycephaly, brachycephaly or mid-face retrusion), trigeminal anesthesia or anatomic abnormalities of the trigeminal nerve. Studies focusing on germline whole genome sequencing or DNA and/or RNA sequencing of the alopecia tissue may be the next step for the better understanding of GLHS etiology.
Asunto(s)
Anomalías Múltiples/genética , Fosfatasa Ácida/genética , Alopecia/genética , Cerebelo/anomalías , Anomalías Craneofaciales/genética , Secuenciación del Exoma , Trastornos del Crecimiento/genética , Síndromes Neurocutáneos/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Adolescente , Adulto , Alopecia/diagnóstico , Alopecia/diagnóstico por imagen , Alopecia/patología , Brasil/epidemiología , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Niño , Preescolar , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/diagnóstico por imagen , Anomalías Craneofaciales/patología , Femenino , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/diagnóstico por imagen , Trastornos del Crecimiento/patología , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Síndromes Neurocutáneos/diagnóstico , Síndromes Neurocutáneos/diagnóstico por imagen , Síndromes Neurocutáneos/patología , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Rombencéfalo/diagnóstico por imagen , Rombencéfalo/patología , Nervio Trigémino/diagnóstico por imagen , Nervio Trigémino/metabolismo , Nervio Trigémino/patología , Adulto JovenRESUMEN
Several patients with 5p duplication or 15q deletion have been reported in the literature, involving different chromosome regions and clinical features. Here, we describe a family in which we identified a 30-Mb 5p15.33p13.3 gain and a 2.5-Mb 15q26.3 loss in 3 individuals, due to a balanced familial translocation between chromosomes 5p and 15q. They presented a similar combination of clinical findings related to their genetic imbalances, but there were also phenotypic differences between them. Our analyses show that their clinical picture is mostly caused by the loss in 15q and not the gain in 5p, despite its much larger size. Our findings suggest that other genes, besides the IGF1R gene, in the 15q26.3 region, such as the CHSY1 gene, may have a great impact on the clinical picture of the syndrome. Our data emphasize the importance of detailed cytogenomic and clinical analyses for an accurate diagnosis, prognosis, and genetic counseling, providing an opportunity to improve genotype-phenotype correlations of patients with partial 5p duplication and 15q deletion syndromes.
RESUMEN
Schmid metaphyseal chondrodysplasia is a rare genetic cause of skeletal dysplasia. Patients usually present skeletal abnormalities but no major visceral malformations or intellectual disability. We report a case of a 2-year-old male patient with short stature, progressive genu varum, and waddling gait. Radiographic findings were essential to guide investigation and molecular confirmation, allowing proper treatment and genetic counseling.
RESUMEN
Kenny-Caffey syndrome (KCS) is a rare hereditary skeletal disorder involving hypoparathyroidism. The autosomal dominant form (KCS2), caused by heterozygous pathogenic variants in the FAM111A gene, is distinguished from the autosomal recessive form (KCS1) and Sanjad-Sakati syndrome (SSS), both caused by pathogenic variants in the tubulin folding cofactor E (TBCE) gene, by the absence of microcephaly and intellectual disability. We present a patient with KCS2 caused by a de novo pathogenic variant c.1706G>A (p.Arg569His) in FAM111A gene, presenting intellectual disability and microcephaly, which are considered to be typical signs of SSS. We suggest that KCS1, KCS2, and SSS may not represent mutually exclusive clinical entities, but possibly an overlapping spectrum.
Asunto(s)
Anomalías Múltiples/patología , Enanismo/patología , Trastornos del Crecimiento/patología , Hiperostosis Cortical Congénita/patología , Hipocalcemia/patología , Hipoparatiroidismo/patología , Discapacidad Intelectual/patología , Mutación , Osteocondrodisplasias/patología , Fenotipo , Receptores Virales/genética , Convulsiones/patología , Anomalías Múltiples/genética , Adolescente , Enanismo/complicaciones , Enanismo/genética , Trastornos del Crecimiento/complicaciones , Trastornos del Crecimiento/genética , Humanos , Hiperostosis Cortical Congénita/complicaciones , Hiperostosis Cortical Congénita/genética , Hipocalcemia/complicaciones , Hipocalcemia/genética , Hipoparatiroidismo/complicaciones , Hipoparatiroidismo/genética , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Masculino , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/genética , Convulsiones/complicaciones , Convulsiones/genéticaRESUMEN
Leigh syndrome is an early onset progressive disorder caused by defects in mitochondrial oxidative phosphorylation. Pathogenic variants in nuclear and mitochondrial genes are associated with the syndrome. Homozygous pathogenic variants in the C12orf65 gene impair the mitochondrial oxidative phosphorylation system. We describe a new case of Leigh syndrome caused by a novel pathogenic variant of the C12orf65 gene resulting in the lack of the Gly-Gly-Gln (GGQ) domain in the predicted protein, and review clinical and molecular data from previously reported patients. Our study supports that the phenotype caused by C12orf65 gene variants is heterogeneous and varies from spastic paraparesis to Leigh syndrome. Loss-of-function variants are more likely to cause the disease, and variants affecting the GGQ domain tend to be associated with more severe phenotypes, reinforcing a possible genotype-phenotype correlation.
RESUMEN
Gomez-López-Hernández syndrome (GLHS) is characterized by rhombencephalosynapsis (RES), alopecia, trigeminal anesthesia and a distinctive phenotype, including brachyturricephaly. It has been suggested that GLHS should be considered as part of the spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial anomalies, rather than a distinct entity. To the best of our knowledge, 57 patients with GLHS have been described. Despite its first description in 1979, the etiology of this syndrome remains unknown. Here, we describe, to our knowledge, the first case of a patient with GLHS who was molecularly evaluated and had been prenatally exposed to misoprostol. We also reviewed the clinical and morphological features of the patients described to date to better delineate the phenotype and focus on any evidence for adverse pregnancy outcomes or exposure, including teratogens.
Asunto(s)
Anomalías Múltiples/tratamiento farmacológico , Anomalías Múltiples/genética , Alopecia/genética , Cerebelo/anomalías , Anomalías Craneofaciales/tratamiento farmacológico , Anomalías Craneofaciales/genética , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/genética , Misoprostol/uso terapéutico , Síndromes Neurocutáneos/tratamiento farmacológico , Síndromes Neurocutáneos/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Alopecia/diagnóstico por imagen , Alopecia/tratamiento farmacológico , Alopecia/patología , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Niño , Preescolar , Anomalías Craneofaciales/diagnóstico por imagen , Anomalías Craneofaciales/patología , Femenino , Trastornos del Crecimiento/diagnóstico por imagen , Trastornos del Crecimiento/patología , Humanos , Imagen por Resonancia Magnética , Síndromes Neurocutáneos/diagnóstico por imagen , Síndromes Neurocutáneos/patología , Fenotipo , Rombencéfalo/diagnóstico por imagen , Rombencéfalo/patología , Nervio Trigémino/diagnóstico por imagen , Nervio Trigémino/efectos de los fármacos , Nervio Trigémino/patologíaRESUMEN
Neu-Laxova syndrome (NLS) is a lethal genetic multiple congenital anomaly syndrome of unknown prevalence representing the severe spectrum of serine biosynthesis defects associated with PHGDH, PSAT1, or PSP gene mutations. The purpose of this study was to describe clinical/molecular and pathologic features of a NLS case caused by novel heterozygous missense variant in PHGDH gene identified in his consanguineous parents.
Asunto(s)
Anomalías Múltiples/genética , Encefalopatías/genética , Anomalías Congénitas/genética , Retardo del Crecimiento Fetal/genética , Ictiosis/genética , Deformidades Congénitas de las Extremidades/genética , Microcefalia/genética , Fosfoglicerato-Deshidrogenasa/genética , Mortinato/genética , Anomalías Múltiples/mortalidad , Anomalías Múltiples/patología , Encefalopatías/mortalidad , Encefalopatías/patología , Brasil/epidemiología , Anomalías Congénitas/mortalidad , Anomalías Congénitas/patología , Consanguinidad , Femenino , Retardo del Crecimiento Fetal/mortalidad , Retardo del Crecimiento Fetal/patología , Genes Letales/genética , Predisposición Genética a la Enfermedad , Humanos , Ictiosis/mortalidad , Ictiosis/patología , Deformidades Congénitas de las Extremidades/mortalidad , Deformidades Congénitas de las Extremidades/patología , Microcefalia/mortalidad , Microcefalia/patología , Mutación Missense/genética , Embarazo , Mortinato/epidemiologíaRESUMEN
OBJECTIVE: For every 100 random children diagnosed with autism, at least 20 have morphological abnormalities, often associated with syndromes. Brazil does not have a standardized and validated instrument for morphological physical examination. This study aimed to translate into Brazilian Portuguese and culturally adapt the clinical signs described in the Autism Dysmorphology Measure, as well as validate the instrument in a sample of children with autism. METHODS: The original instrument was translated, culturally adapted, and published in full, following traditional procedures for translation, back-translation, and terminology adaptation according to the Nomina Anatomica. The sample included 62 children from a published multicenter study, with intelligence quotient between 50-69, of both genders, with chronological age between 3-6 years. Two clinical geneticists performed the morphological physical examination, which consisted of investigating 82 characteristics assessing 12 body areas. We used Cohen's Kappa coefficient to evaluate the agreement between the two observers. RESULTS: The final version of the instrument - translated into Brazilian Portuguese and culturally adapted - showed high agreement between the two observers. CONCLUSIONS: The translated instrument meets all international criteria, and minor anomalies and their clinical descriptions were standardized and are recognizable for physicians not specialized in genetics.
Asunto(s)
Adaptación Psicológica/fisiología , Trastorno del Espectro Autista/psicología , Anomalías Congénitas/diagnóstico , Examen Físico/métodos , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Trastorno Dismórfico Corporal/psicología , Brasil/epidemiología , Niño , Preescolar , Anomalías Congénitas/genética , Características Culturales , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , TraduccionesRESUMEN
ABSTRACT Objective: For every 100 random children diagnosed with autism, at least 20 have morphological abnormalities, often associated with syndromes. Brazil does not have a standardized and validated instrument for morphological physical examination. This study aimed to translate into Brazilian Portuguese and culturally adapt the clinical signs described in the Autism Dysmorphology Measure, as well as validate the instrument in a sample of children with autism. Methods: The original instrument was translated, culturally adapted, and published in full, following traditional procedures for translation, back-translation, and terminology adaptation according to the Nomina Anatomica. The sample included 62 children from a published multicenter study, with intelligence quotient between 50-69, of both genders, with chronological age between 3-6 years. Two clinical geneticists performed the morphological physical examination, which consisted of investigating 82 characteristics assessing 12 body areas. We used Cohen's Kappa coefficient to evaluate the agreement between the two observers. Results: The final version of the instrument - translated into Brazilian Portuguese and culturally adapted - showed high agreement between the two observers. Conclusions: The translated instrument meets all international criteria, and minor anomalies and their clinical descriptions were standardized and are recognizable for physicians not specialized in genetics.
RESUMO Objetivo: Entre 100 crianças, não selecionadas, com diagnóstico de autismo, pelo menos 20 apresentam anomalias morfológicas, quase sempre associadas a síndromes. Não há no Brasil instrumento de exame físico morfológico padronizado e validado. O objetivo foi traduzir para o português do Brasil e adaptar culturalmente os sinais clínicos descritos no Autism Dysmorphology Measure, assim como procurar evidências de validade quando aplicado a uma amostra de crianças com autismo. Métodos: Foram feitas a tradução e a adaptação cultural do instrumento original, publicado na íntegra. Foram adotados os procedimentos tradicionais de tradução, retrotradução e adaptação da terminologia segundo a Nomina Anatomica. Foram incluídas na amostra 62 crianças com quociente de inteligência entre 50 e 69, de ambos os sexos, com idade cronológica entre três e seis anos, provenientes de estudo multicêntrico com os procedimentos metodológicos já publicados. O exame físico morfológico foi realizado por dois médicos geneticistas e consistiu na pesquisa de 82 características que avaliam 12 áreas corporais. Para avaliar a concordância entre os dois observadores foi utilizado o coeficiente Kappa de Cohen. Resultados: A versão final do instrumento traduzido e adaptado culturalmente ao português do Brasil mostrou alta concordância entre os dois observadores. Conclusões: O instrumento traduzido preenche todos os critérios propostos internacionalmente e o reconhecimento das anomalias menores e sua descrição clínica estão padronizados e são de fácil reconhecimento aos médicos não especialistas em genética.
Asunto(s)
Humanos , Masculino , Femenino , Preescolar , Niño , Examen Físico/métodos , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/genética , Adaptación Psicológica/fisiología , Trastorno del Espectro Autista/psicología , Traducciones , Brasil/epidemiología , Encuestas y Cuestionarios , Reproducibilidad de los Resultados , Características Culturales , Trastorno Dismórfico Corporal/psicología , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genéticaRESUMEN
Keutel syndrome is caused by mutations in the matrix gamma-carboxyglutamic acid (MGP) gene (OMIM 154870) and is inherited in an autosomal recessive fashion. It is characterized by brachydactyly, pulmonary artery stenosis, a distinctive facial phenotype, and cartilage calcification. To date, only 36 cases have been reported worldwide. We describe clinical and molecular findings of the first Brazilian patient with Keutel syndrome. Keutel syndrome was suspected based on clinical and morphological evaluation, so we sequenced the MGP gene using the TruSight One Sequencing Panel (Illumina). The obtained MGP gene sequence was then validated by Sanger sequencing. We identified a novel pathogenic homozygous variant of the MGP gene (c.2T>C; p.Met1Thr) confirming Keutel syndrome. Proper diagnosis of this syndrome is important for clinical management and is an indication for genetic counseling. Keutel syndrome should be suspected in patients with cartilage calcifications and brachydactyly when associated with a distinctive facial phenotype and pulmonary artery stenosis.
RESUMEN
Abstract Objective: To establish the frequency of 82 morphological features in a sample of Brazilian children (between 3 and 13 years old), to understand the influence of age, gender, and ethnicity. Methods: This was a cross-sectional study that evaluated 239 children with typical development (between 3 and 13 years old) regarding the presence of 82 morphological characteristics. A previously described protocol, based on the London Dysmorphology Database, was applied to evaluate the sample. This protocol was culturally adapted to Brazilian Portuguese. Results: The frequency of 82 morphological characteristics was established in the sample; of 82 characteristics, 50% were considered morphological anomalies (frequency less than 4%). At least 25% of the sample presented more than one minor morphological anomaly. Age was shown to influence the frequency of the following morphological characteristics: widow's peak, prominent antihelix, prominent upper lip, irregular or crowded teeth, and clinodactyly, but had no influence on the frequency of minor morphological anomalies. Gender influenced dysplastic ears and attached earlobe, but had no influence on the frequency of minor morphological anomalies; ethnicity showed influence on camptodactyly and prominent antihelix. A statistically significant divergence was observed regarding 43 of the 73 morphological characteristics that could be compared with literature data (58.9%). Conclusions: The study determined the frequency of 82 morphological characteristics in 239 children with typical development. Age was the variable that showed more influence on the frequency of morphological characteristics, and comparison with literature data showed that the frequency depends on variables such as age and ethnicity.
Resumo Objetivo: Estabelecer a frequência de 82 características morfológicas em uma amostra de crianças brasileiras (entre três e 13 anos), para entender a influência da idade, do sexo e da etnia. Métodos: Estudo transversal. Avaliamos 239 crianças com desenvolvimento típico (entre três e 13 anos), em relação à presença de 82 características morfológicas. Aplicamos um protocolo descrito anteriormente, baseado no London Dysmorphology Database, para avaliar nossa amostra. Esse protocolo foi culturalmente adaptado ao português do Brasil. Resultados: A frequência de 82 características morfológicas foi estabelecida em nossa amostra; de 82 características, 50% foram consideradas anomalias morfológicas (frequência inferior a 4%). Pelo menos 25% da nossa amostra apresentaram mais de uma anomalia morfológica menor. A idade mostrou influência na frequência das seguintes características morfológicas: "bico de viúva", "anti-hélice proeminente", "lábio superior proeminente", "dentes irregulares ou encavalados" e "clinodactilia", mas não teve influência na frequência de anomalias morfológicas menores. O sexo mostrou influência nas seguintes características: "orelhas displásicas" e "lóbulo da orelha aderente", mas não teve influência na frequência de anomalias morfológicas menores; a etnia mostrou influência na "camptodactilia" e "anti-hélice proeminente". Houve divergência (estatisticamente significativa) em 43 características morfológicas de 73 que pudemos comparar com os dados da literatura (58,9%). Conclusões: Estabelecemos a frequência de 82 características morfológicas em 239 crianças com desenvolvimento típico. A idade foi a variável que mostrou maior influência na frequência de características morfológicas e a comparação com dados da literatura mostrou que a frequência depende de variáveis como idade e etnia.