Allan-Herndon-Dudley syndrome in a female patient and related mechanisms.

peer reviewedAllan-Herndon-Dudley syndrome (AHDS) is characterized by neuropsychomotor developmental delay/intellectual disability, neurological impairment with a movement disorder, and an abnormal thyroid hormone profile. This disease is an X-linked disorder that mainly affects men. We described a female patient with a de novo variant in the SLC16A2 gene, a milder AHDS phenotype, and a skewed X chromosome inactivation profile. We discuss the mechanisms associated with the expression of the phenotypic characteristics in female patients, including SLC16A2 gene variants and cytogenomic alterations, as well as preferential inactivation of the normal X chromosome

Pseudohipoaldosteronism Type 1: a case report supported by a literature review

In the neonatal period, hydro electrolytic disorders with dehydration and metabolic acidosis can cause admission to an intensive care unit and become a diagnostic challenge. Among such disorders, hyponatremia and hyperkalemia become diagnostic challenges with hormonal involvement, including aldosterone. Pseudohypoaldosteronism (PHA) resulting from the lack of response to aldosterone in target cells can be classified into three types and its suspected diagnosis in cases of hyponatremia, hyperkalemia with an elevation of serum aldosterone, can be confirmed by exome sequencing with identification of a potentially pathogenic. This study was based on the case report of a newborn of consanguineous parents who, after birth, evolved in the first week of life with shock, hyponatremia, hyperkalemia, and metabolic acidosis. An initial investigation ruled out congenital adrenal hyperplasia. The presence of hyperaldosteronism with increased plasma renin activity, associated with hyperkalemia and hyponatremia difficult to control with electrolyte replacement, led to a molecular investigation that confirmed PHA type 1 by a mutation in the SCCN1A gene. In neonates with severe hyponatremia that is difficult to resolve with conventional treatment and elevation of serum aldosterone, this pathology must be remembered and investigated, avoiding high morbidity and mortality

Cytogenomic assessment of the diagnosis of 93 patients with developmental delay and multiple congenital abnormalities: The Brazilian experience

OBJECTIVE: The human genome contains several types of variations, such as copy number variations, that can generate specific clinical abnormalities. Different techniques are used to detect these changes, and obtaining an unequivocal diagnosis is important to understand the physiopathology of the diseases. The objective of this study was to assess the diagnostic capacity of multiplex ligation-dependent probe amplification and array techniques for etiologic diagnosis of syndromic patients. METHODS: We analyzed 93 patients with developmental delay and multiple congenital abnormalities using multiplex ligation-dependent probe amplifications and arrays. RESULTS: Multiplex ligation-dependent probe amplification using different kits revealed several changes in approximately 33.3% of patients. The use of arrays with different platforms showed an approximately 53.75% detection rate for at least one pathogenic change and a 46.25% detection rate for patients with benign changes. A concomitant assessment of the two techniques showed an approximately 97.8% rate of concordance, although the results were not the same in all cases. In contrast with the array results, the MLPA technique detected ∼70.6% of pathogenic changes. CONCLUSION: The obtained results corroborated data reported in the literature, but the overall detection rate was higher than the rates previously reported, due in part to the criteria used to select patients. Although arrays are the most efficient tool for diagnosis, they are not always suitable as a first-line diagnostic approach because of their high cost for large-scale use in developing countries. Thus, clinical and laboratory interactions with skilled technicians are required to target patients for the most effective and beneficial molecular diagnosis

Clinical and molecular cytogenetics investigation in patients with psychomotor delay associated with congenital malformation

Introdução: Com a sofisticação das técnicas de análise do DNA, a medicina moderna tem à sua disposição boas possibilidades para elucidar quadros clínicos indefinidos em pacientes que possuem microrrearranjos cromossômicos complexos. O desenvolvimento da técnica de MLPA (Multiplex ligation-dependent probe amplification) aliado à tecnologia dos arrays (WGAS - whole genome array screening) possibilitou analisar de uma só vez, diferentes regiões de interesse clínico no genoma humano. Objetivo: O presente trabalho teve como objetivo estudar pacientes com atraso de desenvolvimento neuropsicomotor (ADNPM) associado à malformação congênita (MC) com cariótipo prévio normal ou inconclusivo. Material e métodos: Participaram do estudo 71 pacientes com ADNPM associado à MC que foram analisados utilizando o teste de MLPA com os kits P036 e P064, seguido de WGAS com as diferentes plataformas (Agilent, Affymetrix e Illumina). Resultados: Entre os 33 pacientes com alterações patogênicas e de significado clínico incerto (VOUS) encontramos: 12 pacientes com deleção, 5 com duplicação e 16 com duplicações e deleções (dup/del) concomitantes. Foram 29 pacientes com alterações patogênicas conclusivas, 4 pacientes com CNVs classificadas como VOUS e 15 pacientes tiveram resultado de array normal além dos outros 23 que apresentaram alterações benignas, ou por não apresentarem genes na região alterada, ou por serem genes sem fenótipos descritos, ou ainda, as alterações foram herdadas de genitores normais. Na casuística total foram encontrados 4 pacientes com regiões de perda de heterozigosidade. Conclusões: A utilização de uma estratégia combinada utilizando diferentes kits de MLPA, com capacidade para detectar as principais microalterações genômicas patogênicas conhecidas, associada à aplicação do WGAS possibilitou a detecção de alterações submicroscópicas, bem como a correlação clínica adequada para pacientes não diagnosticados pela citogenética clássica. Dessa forma, nosso estudo sugere um novo modelo para a aplicação combinada desses testes que representa uma alternativa de bom custo-benefício para a triagem genômica e definição diagnóstica dos pacientes com quadros sindrômicos complexos e suas famíliasIntroduction: The recent technological advances on DNA-based techniques have established in modern medicine good opportunities to elucidate undefined clinical cases in patients with complex chromosomal microrearrangements. The performance of MLPA (Multiplex ligation-dependent probe amplification) technique together with array technologies (WGAS - whole genome array screening) created the possibility of one single experiment to analyze different regions of interest in the human genome. Objective: Patients with psychomotor delay (PSMD) associated with multiple congenital anomalies who had normal or inconclusive G-band-karyotype (MCA) were studied in order to understand the genotype-phenotype correlations. Material and methods: This study involved 71 patients with psychomotor delay (PSMD) associated with multiple congenital anomalies (MCA) analyzed by MLPA (P036 and P064 kits), followed by WGAS different platforms (Agilent, Affymetrix e Illumina®). Results: Among 33 patients with pathogenic and uncertain (VOUS) copy number variations (CNV) were found: 12 deletions, 5 duplications and 16 concomitant duplication and deletion (dup/del). There were 29 patients with conclusive pathogenic findings, 4 patients with VOUS and 16 patients with normal array, but others 23 patients with benign results, which means there is no gene content in the region involved, or because these genes were not linked to phenotype, or even due to CNVs inherited of healthy parents. From the whole casuistic, 4 individuals presented loss of heterozygosity (LOH) regions. Conclusions: The use of a combined strategy of analysis (MLPA - WGAS) with a high capacity to detect pathogenic CNVs allows unraveling microscopic imbalances, and consequently, offers an adequate clinical correlation for patients not previously diagnosed by classical cytogenetics. In conclusion, this study suggests a new model for the combined application of these techniques, which represents an optimal alternative for a genomic screening and diagnostic establishment in patients with rare complex disorders and their familie

CEDNIK syndrome in a Brazilian patient with compound heterozygous pathogenic variants.

peer reviewedCEDNIK (Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome is a neuro ichthyotic syndrome characterized by a clinical constellation of features including severe developmental delay, microcephaly, and facial dysmorphism. Here, we report the clinical and molecular characterization of a patient with CEDNIK syndrome harboring two compound heterozygous variants in the SNAP29 gene. The patient presents a combination of a loss-of-function SNAP29 mutation and a ∼370 kb 22q11.2 deletion, each of these genetic variants inherited from one of the parents. This report provides detailed data of a patient with unprecedented genetic events leading to the CEDNIK phenotype and may contribute to the elucidation of this rare condition

Cytogenomic characterization of an unexpected 17.6 Mb 9p deletion associated to a 14.8 Mb 20p duplication in a dysmorphic patient with multiple congenital anomalies presenting a normal G-banding karyotype

We describe a female patient with developmental delay, dysmorphic features and multiple congenital anomalies who presented a normal G-banded karyotype at the 550-band resolution. Array and multiplex-ligation probe amplification (MLPA) techniques identified an unexpected large unbalanced genomic aberration: a 17.6 Mb deletion of 9p associated to a 14.8 Mb duplication of 20p. The deleted 9p genes, especially CER1 and FREM1, seem to be more relevant to the phenotype than the duplicated 20p genes. This study also shows the relevance of using molecular techniques to make an accurate diagnosis in patients with dysmorphic features and multiple anomalies suggestive of chromosome aberration, even if on G-banding their karyotype appears to be normal. Fluorescence in situ hybridization (FISH) was necessary to identify a masked balanced translocation in the patient's mother, indicating the importance of associating cytogenetic and molecular techniques in clinical genetics, given the implications for patient management and genetic counseling. (C) 2012 Elsevier B.V. All rights reserved.FAPESP (Brazil) [10/50737-1]FAPESP (Brazil

Cytogenomic assessment of the diagnosis of 93 patients with developmental delay and multiple congenital abnormalities: The Brazilian experience

OBJECTIVE: The human genome contains several types of variations, such as copy number variations, that can generate specific clinical abnormalities. Different techniques are used to detect these changes, and obtaining an unequivocal diagnosis is important to understand the physiopathology of the diseases. The objective of this study was to assess the diagnostic capacity of multiplex ligation-dependent probe amplification and array techniques for etiologic diagnosis of syndromic patients. METHODS: We analyzed 93 patients with developmental delay and multiple congenital abnormalities using multiplex ligation-dependent probe amplifications and arrays. RESULTS: Multiplex ligation-dependent probe amplification using different kits revealed several changes in approximately 33.3% of patients. The use of arrays with different platforms showed an approximately 53.75% detection rate for at least one pathogenic change and a 46.25% detection rate for patients with benign changes. A concomitant assessment of the two techniques showed an approximately 97.8% rate of concordance, although the results were not the same in all cases. In contrast with the array results, the MLPA technique detected ∼70.6% of pathogenic changes. CONCLUSION: The obtained results corroborated data reported in the literature, but the overall detection rate was higher than the rates previously reported, due in part to the criteria used to select patients. Although arrays are the most efficient tool for diagnosis, they are not always suitable as a first-line diagnostic approach because of their high cost for large-scale use in developing countries. Thus, clinical and laboratory interactions with skilled technicians are required to target patients for the most effective and beneficial molecular diagnosis