Novel Pathogenic Mutation Mapping of ASPM Gene in Consanguineous Pakistani Families with Primary Microcephaly / Novo mapeamento de mutações patogênicas do gene ASPM em famílias consanguíneas com microcefalia primária do Paquistão

Abstract Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a congenitally reduced head circumference (-3 to -5 SD) and non-progressive intellectual disability. The objective of the study was to evaluate pathogenic mutations in the ASPM gene to understand etiology and molecular mechanism of primary microcephaly. Blood samples were collected from various families across different remote areas of Pakistan from February 2017 to May 2019 who were identified to be affected with primary microcephaly. DNA extraction was performed using the salting-out method; the quality and quantity of DNA were evaluated using spectrophotometry and 1% agarose gel electrophoresis, respectively in University of the Punjab. Mutation analysis was performed by whole exome sequencing from the Cologne Center for Genomics, University of Cologne. Sanger sequencing was done in University of the Punjab to confirm the pathogenic nature of mutation. A novel 4-bp deletion mutation c.3877_3880delGAGA was detected in exon 17 of the ASPM gene in two primary microcephaly affected families (A and B), which resulted in a frame shift mutation in the gene followed by truncated protein synthesis (p.Glu1293Lysfs*10), as well as the loss of the calmodulin-binding IQ domain and the Armadillo-like domain in the ASPM protein. Using the in-silico tools Mutation Taster, PROVEAN, and PolyPhen, the pathogenic effect of this novel mutation was tested; it was predicted to be "disease causing," with high pathogenicity scores. One previously reported mutation in exon 24 (c.9730C>T) of the ASPM gene resulting in protein truncation (p.Arg3244*) was also observed in family C. Mutations in the ASPM gene are the most common cause of MCPH in most cases. Therefore, enrolling additional affected families from remote areas of Pakistan would help in identifying or mapping novel mutations in the ASPM gene of primary microcephaly.

Resumo Microcefalia primária autossômica recessiva (MCPH) é um distúrbio do neurodesenvolvimento caracterizado por uma redução congênita do perímetro cefálico (-3 a -5 DP) e deficiência intelectual não progressiva. O objetivo do estudo foi avaliar mutações patogênicas no gene ASPM a fim de compreender a etiologia e o mecanismo molecular da microcefalia primária. Amostras de sangue foram coletadas de várias famílias em diferentes áreas remotas do Paquistão de fevereiro de 2017 a maio de 2019, que foram identificadas como afetadas com microcefalia primária. A extração do DNA foi realizada pelo método salting-out; a qualidade e a quantidade de DNA foram avaliadas por espectrofotometria e eletroforese em gel de agarose a 1%, respectivamente, na Universidade de Punjab. A análise de mutação foi realizada por sequenciamento completo do exoma do Cologne Center for Genomics, University of Cologne. O sequenciamento de Sanger foi feito na Universidade do Punjab para confirmar a natureza patogênica da mutação. Uma nova mutação de deleção de 4 bp c.3877_3880delGAGA foi detectada no exon 17 do gene ASPM em duas famílias afetadas por microcefalia primária (A e B), que resultou em uma mutação de frame shift no gene seguida por síntese de proteína truncada (pGlu1293Lysfs * 10), bem como a perda do domínio IQ de ligação à calmodulina e o domínio do tipo Armadillo na proteína ASPM. Usando as ferramentas in-silico Mutation Taster, PROVEAN e PolyPhen, o efeito patogênico dessa nova mutação foi testado; foi previsto ser "causador de doenças", com altos escores de patogenicidade. Uma mutação relatada anteriormente no exon 24 (c.9730C > T) do gene ASPM, resultando em truncamento de proteína (p.Arg3244 *) também foi observada na família C. Mutações no gene ASPM são a causa mais comum de MCPH na maioria dos casos . Portanto, a inscrição de famílias afetadas adicionais de áreas remotas do Paquistão ajudaria a identificar ou mapear novas mutações no gene ASPM da microcefalia primária.

A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family / 亚洲男科学杂志(英文版)

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate. Whole-exome sequencing (WES) is used to detect pathogenic variants in patients with MMAF. In this study, a novel homozygous frameshift variant (c.6158_6159insT) in dynein axonemal heavy chain 8 (DNAH8) from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed DNAH8 mRNA decay in these patients with the DNAH8 mutation. Hematoxylin-eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients. Furthermore, an immunofluorescence assay showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients' spermatozoa. Collectively, our study expands the phenotypic spectrum of patients with DNAH8-related MMAF worldwide.

Agregación familiar y factores de riesgo de asma bronquial en individuos afectados / Familial aggregation and risk factors for bronchial asthma in affected individuals

Introducción: La agregación familiar del asma se reconoce desde 1 860 a constatarse en varias generaciones de una familia. Objetivo: Determinar la agregación familiar para asma bronquial y los factores de riesgo. Material y Métodos: Se realizó una investigación observacional, analítica, longitudinal, retrospectiva, casos/control a partir de la población perteneciente al área de salud Darío Calzadilla, en Banes, provincia Holguín, durante octubre 2020-marzo 2021. El universo abarcó la totalidad de individuos diagnosticados y sus familias. Por muestreo aleatorio simple, se obtuvo la muestra de 77 casos. Se conformó el grupo control a razón de 3:1, que incluyó 231 individuos sin antecedentes de enfermedad. Fueron aplicados criterios de inclusión/exclusión. Fueron utilizados los estadígrafos: Chi cuadrado, Odd Ratio (OR) e intervalo de confianza. Se estudiaron las variables: edad, grado de consanguinidad y factores de riesgo. Se obtuvo el árbol genealógico. Se cumplieron los requisitos bioéticos. Resultados: Los familiares de primer grado (47 individuos 17 por ciento) y segundo grado (23 individuos 4,3 por ciento) de consanguinidad mostraron la mayor incidencia de la enfermedad. Los grupos de edades 40-49 años (51 individuos, 22,8 por ciento) y 30-39 años (32 individuos, 22,3 por ciento), resultaron los más afectados. Los factores de riesgos mostraron asociación para la enfermedad (X2=111,15 p ≤ 0,001). El hábito de fumar (X2=132,9 OR=6,18 IC95 por ciento (4,49; 8,51)) y los antecedentes familiares de la enfermedad (X2=13,6 OR=1,73 IC95 por ciento (1,29; 2,32)) expresaron asociación altamente significativa. Se demostró agregación familiar para la enfermedad (X2=185,32 OR=9,97 IC95 por ciento (6,7; 14,84)). Conclusiones: El asma bronquial es una enfermedad multifactorial, compleja, poligénica con agregación familiar demostrada(AU)

Introduction: Familial aggregation of asthma has been recognized since 1860 and observed in several generations in one family. Objective: To determine familial aggregation of bronchial asthma as well as its risk factors. Material and Methods: An observational, analytical, longitudinal, and retrospective case-control study was conducted on the population belonging to Darío Calzadilla health area in Banes, Holguín province, from October 2020 to March 2021. The universe consisted of all the individuals diagnosed and their families. A sample composed of 77 cases was obtained by simple random sampling. The control group was formed at a ratio of 3:1, including 231 individuals without previous history of the disease. Inclusion and exclusion criteria were applied. The following stadigraphs were used: Chi-square test, Odds Ratio (OR), and confidence interval. The variables analyzed included age, degree of consanguinity, and risk factors. The family tree was obtained. Bioethical principles were fulfilled. Results: The first-degree relatives (47 individuals; 17 percent) and second-degree (23 individuals; 4,3 percent) of consanguinity showed a higher incidence of the disease. The age group 40-49 years (51 individuals; 22,8 percent) and 30-39 years (32 individuals; 22,3 percent), resulted to be the most affected. The risk factors evidenced an association with the disease (X2=111,15 p≤0,001). The smoking habit (X2=132,9 OR=6,18 95 percent CI (4,49; 8,51)) and family history of the disease (X2=13,6 OR=1,73 95 percent CI (1,29; 2,32)) expressed a highly significant association. Familial aggregation of the disease was demonstrated (X2=185,32 OR=9,97 95 % CI (6,7;14,84)). Conclusions: Bronchial asthma is a complex, multifactorial, polygenic disease with confirmed familial aggregation(AU)

Família na visão dos psicólogos do CRAS / Family from the point of view of CRAS psychologists

Este estudo buscou investigar as concepções de família de psicólogos dos Centros de Referência de Assistência Social (CRAS). Para isso, foram realizadas entrevistas individuais com cinco psicólogos inseridos nos CRAS de uma cidade do Rio Grande do Sul, a fim de acessar suas crenças, valores e representações envolvendo o conceito de família. A partir da análise qualitativa de conteúdo, os resultados indicaram que os participantes consideraram família as pessoas que estabelecem relações a partir de laços afetivos, não restringindo sua definição à consanguinidade. Ainda, apontaram como indicadores de saúde familiar a capacidade de cuidar dos filhos, manejar conflitos e a não violência. Todavia, alguns participantes apresentaram resquícios de uma visão de família tradicional e romantizada. Ressalta-se a importância de a atuação do psicólogo estar atrelada à capacidade de analisar criticamente o contexto de atuação e a realidade social brasileira. A partir disso, espera-se contribuir para a construção de uma prática que não reproduza a violência social e a estigmatização das famílias atendidas.

This study sought to investigate the family conceptions of psychologists at the Social Assistance Reference Centers (CRAS). For this, individual interviews were conducted with five psychologists inserted in the CRAS of a city of Rio Grande do Sul, in order to access their beliefs, values ​​and representations involving the concept of family. From the qualitative analysis of content, the results indicated that the participants considered family the persons who establish relationships based on emotional ties, not restricting their definition to consanguinity. In addition, they pointed out as indicators of family health the ability to take care for children, handle conflicts and non-violence. However, some participants presented traces of a traditional and romanticized family view. The importance of the psychologist's performance is linked to the ability to critically analyze the context of practice and the Brazilian social reality. From this, it is expected to contribute to the construction of a practice that does not reproduce social violence and stigmatization of the families served.

Nexo epidemiológico en niños con diagnóstico de COVID-19. Hospital General del Sur de Quito. 2020 / Epidemiological link in children with diagnosis of COVID-19. Hospital General del Sur de Quito. 2020

Introducción: Los niños con COVID-19 han mostrado antecedentes claros de agrupamiento en infectados en el hogar y comunidad extendida, por lo que es interesante identificar el nexo epidemiológico (contactos) por grados de consanguinidad de casos positivos para COVID-19, desde el punto de vista de prevención de la enfermedad. Método: Estudio descriptivo, retrospectivo de tipo transversal, muestreo no probabilístico, que incluyó 54 niños con infección confirmada por el virus SARS-CoV-2, atendidos en la Emergencia Pediátrica del Hospital General del Sur de Quito durante los meses de abril a junio 2020. Los datos se obtuvieron del sistema de historias clínicas AS400. El análisis se realizó con el programa estadístico SPSS. Se determinaron porcentajes en las variables nominales. Resultados: Se incluyeron 54 niños, la mayoría adolescentes de 10 a 14 años (27,8%), predominó el sexo masculino (55,6%). El 79,65% tuvo contacto con personas COVID-19. El 53,5% tuvo solo un contacto directo, mientras que el resto, dos o más contactos. El nexo epidemiológico de contagio primario correspondió a la madre (32,55%). Conclusión: La investigación arrojó que el sexo masculino, los escolares y adolescentes fueron los más afectados por COVID-19. Por otra parte, el primer contacto con personas enfermas fue un miembro de la familia que, en su mayoría, correspondió a uno o ambos padres. No está claro si algún niño presentó la infección antes que el resto de miembros de la familia.Palabras claves: COVID-19, nexo epidemiológico, grado de consanguinidad, transmisión, contacto

ABSTRACTIntroduction: Children with COVID-19 have shown a clear history of infected grouping at home and in their extended community, that is why it is very inter-esting to define and identify the epidemiological links evidenced in pediatric patients, from the point of view of disease prevention. Objective: To know the epidemiological links of pediatric patients between 1 month and 17 years old with positive result to the Reverse Polymerase Chain Reaction (RT-PCR) test for SARS-CoV-2. Method: Descriptive, retrospective, cross-sectional study, which included 54 children with confirmed infection by the SARS-CoV-2 virus, treated at the Pediatric Emergency of the General Hospital of the South of Quito during the months of April to June 2020. The data was obtained from the AS400 system. The analysis was performed with the SPSS statistical program; percentages were determined in the nominal variables. Results: 54 children were included, most of them adolescents from 10 to 14 years old (27,8%), the male sex predominated (55,6%). 79,65%, had contact with COVID-19 infected people. 53,50% had only one direct contact, while the rest had two or more contacts, 20,95% and 25,55% respectively. The epidemiological nexus for primary contagion corresponds to the mother (32,55%). Conclusion: The research showed that males, school-age children, and adolescents were the most affected by COVID-19. On the other hand, the first contact with sick people was a family member that mostly corresponded to one or both parents. It is not clear if any child developed the infection earlier than other family members.

La endogamia como causa de consanguinidad y su asociación con anomalías congénitas / Endogamy as a cause of consanguinity and its association with congenital anomalies

El papel de la endogamia como causa de homocigosidad en la salud humana es un foco de interés en genética médica, debido a su relación con anomalías congénitas y patologías genéticas recesivas. Es un tema importante a pesar de que las tasas de uniones consanguíneas en ciertas sociedades han disminuido con el tiempo; sin embargo, en algunas comunidades se han mantenido estables o han aumentado. La consanguinidad es practicada hasta en el 10% de la población mundial, y los motivos más comúnmente citados son socioculturales y socioeconómicos. Aunque se ha visto una disminución de esta práctica, probablemente por la migración urbana y el aumento de las tasas de educación, la consanguinidad continúa practicándose en todo el mundo. Los efectos más significativos sobre los resultados reproductivos se deben, principalmente, a condiciones hereditarias autosómicas recesivas, que también aumentan la frecuencia de algunos desórdenes médicos. El objetivo de esta revisión es dar a conocer la epidemiología y los factores predisponentes de la consanguinidad, así como presentar la evidencia actual de la asociación entre la consanguinidad originada en la endogamia y las anormalidades congénitas y patologías médicas como consecuencia de trastornos genéticos mendelianos. Se requiere un enfoque culturalmente apropiado para el asesoramiento genético en relación con la endogamia

The role of consanguinity as a cause of homozygosity in human health is a focus of interest in medical genetics, due to its relationship with congenital anomalies and recessive genetic pathologies. This is an important issue since the rates of consanguineous unions in certain societies have decreased over time, but have remained stable or have increased in others. Consanguinity is practiced in up to 10% of the world population, and the most common reasons are sociocultural and socioeconomic factors. Although there has been a decrease in this practice, probably due to urban migration and an increase in education rates, consanguinity continues to be practiced throughout the world. The most significant effects on reproductive outcomes are mainly due to autosomal recessive hereditary conditions, that also increase the frequency of medical disorders. The aim of this review is to present the current evidence of the association between consanguinity originating from endogamy, with congenital abnormalities and medical disorders originated from mendelian genetic pathologies. A cultural appropriate approach is required for genetic counseling in relation to consanguineous endogamy

Study on TYR gene variant from a pedigree with oculocutaneous albinism / 中华医学遗传学杂志

OBJECTIVE@#To analyze gene variants in a Chinese pedigree with oculocutaneous albinism (OCA).@*METHODS@#Gene sequencing of the proband and his parents was performed using chip capture high-throughput sequencing and Sanger sequencing techniques, and PolyPhen-2, SIFT, MutationTaster, and FATHMM software were used to predict the function of new variants. At the same time,the pedigree and variant genes of 4 albinism patients from this pedigree were analyzed.@*RESULTS@#Sequencing results showed that the proband's TYR gene (NM_000372) has c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) compound heterozygous variants. The proband's father carries c.230G>A heterozygous variant, and the mother carries c.120_121insG heterozygous variant, indicating that the proband's two variants are from his father and mother. The former is a known missense variant, which can cause abnormal or loss of the original function of the protein polypeptide chain. The latter c.120_121insG(p.Asp42GlyfsTer35) is an unreported frameshift variant of the TYR gene subregion (EX1; CDS1). PolyPhen-2, SIFT, MutationTaster and FATHMM predictions are all prompted as "harmful variants". This variant caused the amino acid encoded protein to terminate prematurely, producing a truncated protein, which eventually formed a 76-amino acid short-type TYR protein instead of the 529-amino acid wild-type TYR protein. Through the pedigree analysis, the four patients in the pedigree are all of the same type of compound heterozygous variants, and the disease-causing genes are all from the patient's parents. They belong to a special form of consanguineous marriage within 5 generations.@*CONCLUSION@#The compound heterozygous variants of c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) of the TYR gene may underlie the disease in this pedigree. The gene sequencing results enrich the variant spectrum of the TYR gene, and has facilitated molecular diagnosis for the patient.

Identification of a novel variant of F5 gene in a consanguineous pedigree affected with inherited coagulation factor V deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a consanguineous pedigree affected with inherited coagulation factor V deficiency.@*METHODS@#Genomic DNA was extracted from peripheral blood samples from the pedigree and subjected to next generation sequencing for screening variants of the F5 gene. Suspected pathogenic variant was verified by using Sanger sequencing. Pathogenicity of the variant was evaluated according to ACMG guidelines.@*RESULTS@#A homozygous frameshifting variant, c.4096delC (p.Leu1366Phefs*3), was identified in the F5 gene in the proband, which was confirmed to be derived from her consanguineous parents. This variant was absent in all databases including 10 000 in-house Chinese exome sequences. Based on the ACMG guidelines, the c.4096delC was predicted to be a pathogenic variant.@*CONCLUSION@#A novel pathogenic variant has been identified in the F5 gene in a consanguineous pedigree with inherited coagulation factor V deficiency, which has enriched the spectrum of F5 gene variants.

Impacto de la consanguinidad en la descendencia de matrimonios consanguíneos / Impact of Consanguinity in the Offspring of Consanguineous Marriages

Introducción: La consanguinidad continúa siendo un fenómeno universal, hoy día los matrimonios consanguíneos y su descendencia suponen aproximadamente el 10,4 por ciento de la población mundial; sus descendientes tienen una elevada probabilidad de padecer enfermedades mendelianas recesivas, así como enfermedades complejas de naturaleza multifactorial. Objetivos: Determinar el coeficiente de endogamia de la región y las principales afectaciones encontradas en la descendencia de matrimonios consanguíneos. Métodos: Se realizó una investigación descriptiva, aplicada y retrospectiva de corte transversal sobre coeficiente de endogamia en el Consejo Popular Paso Quemado, municipio Los Palacios, Pinar del Río, en el período comprendido entre mayo 2016 y febrero 2017. Resultados: Fueron identificados 11 matrimonios consanguíneos (1,96 por ciento), mayormente en área rural y entre primos hermanos. El coeficiente de endogamia medio fue 0,00115. Después de la década del 70 no se efectuaron matrimonios consanguíneos. Afectaciones como mortalidad infantil, enfermedades monogénicas raras, malformaciones congénitas, discapacidad intelectual leve y enfermedades comunes aparecieron con mayor frecuencia en la descendencia de primos hermanos. Conclusiones: En correspondencia con la apertura de nuevas oportunidades sociales, económicas y educativas en la región la consanguinidad no constituye hoy en día un problema de salud, no obstante 52,5 por ciento de la descendencia en consanguíneos resultó afectada, mayormente por enfermedades complejas. El estudio sienta las bases para establecer una estrategia de educación y promoción de salud a nivel comunitario(AU)

Introduction: Consanguinity continues to be a universal phenomenon. Nowadays, consanguineous marriages and their descendants are estimated at 10,4 percent of the world population; their descendants have a high probability of suffering recessive Mendelian diseases, as well as complex diseases of multifactorial nature. Objectives: To determine the inbreeding coefficient of the region and the main affectations found in offspring of consanguineous marriages. Methods: A descriptive, applied and retrospective cross-sectional research on the inbreeding coefficient was conducted at Paso Quemado Popular Council, Los Palacios Municipality, Pinar del Río, from May 2016 to February 2017. Results: We identified 11 consanguineous marriages (1.96 percent), mostly in rural areas and among first cousins. The average inbreeding coefficient was 0.00115. After the 70's, there was no occurrence of consanguineous marriages. Affectations such as infant mortality, rare monogenic diseases, congenital malformations, mild intellectual disability and common diseases appeared more frequently in the offspring of first cousins. Conclusions: In correspondence with the opening of new social, economic and educational opportunities in the region, consanguinity does not constitute a health problem nowadays; however, mostly complex diseases affected 52.5 percent of offspring in consanguineous couples. The study lays the foundations to establish a health education and promotion strategy at the community level(AU)

Tumores renales pediátricos y su posible asociación con poblaciones endogámicas en el centro de Argentina / Pediatric renal tumors and their possible relation with endogamous populations in central Argentina

Introducción: Existen pocas investigaciones sobre factores de riesgo de tumores renales pediátricos. Objetivo: Caracterizar en detalle regiones geográficas de alta incidencia de tumores renales pediátricos en el centro de Argentina y su posible vinculación con factores de riesgo genéticos. Métodos: El área de estudio comprendió la provincia de Córdoba (Argentina). Se generó una base de datos de incidencia del cáncer renal infantil con información del Registro Provincial de Tumores. Se realizaron análisis de conglomerados espaciotemporales. En localidades dentro de los conglomerados, se llevaron a cabo entrevistas en profundidad a informantes claves. Resultados: Se registraron 56 casos de tumores renales pediátricos en el Registro en el periodo 2004-2013. Se detectó un conglomerado espacial significativo que abarca siete departamentos de la provincia. En esa región se concretaron seis entrevistas en profundidad a informantes claves. Los entrevistados resaltaron la mayor frecuencia de enfermedad genética de Sandhoff y las prácticas de endogamia (corroboradas en numerosos resultados científicos). A partir de estos datos se determinaron zonas de superposición de tumores renales y de la enfermedad de Sandhoff. Conclusiones: Se detectó una región particular de la provincia con alta frecuencia de tumores renales pediátricos y de la enfermedad de Sandhoff. Numerosos estudios científicos determinan que la endogamia es el factor de riesgo que aumenta la frecuencia de esta enfermedad en esta región. En futuras investigaciones se deberá corroborar si la endogamia también actúa aumentando la incidencia de tumores renales infantiles(AU)

Introduction: There is little research on risk factors of pediatric renal tumors. Objective: To characterize in detail the geographic regions of greatest incidence of pediatric renal tumors in central Argentina and exploring their possible link to genetic risk factors. Methods: The study area comprised the province of Córdoba (Argentina), and a database of pediatric renal tumors incidence was generated with information from the Provincial Tumor Registry. Analyses of spatio-temporal clusters were performed. In-depth interviews with key informants were carried out at localities within the conglomerates. Results: 56 cases of pediatric renal tumors were registered in the Provincial Registry of Tumors between 2004 and 2013. A significant spatial conglomerate was detected, covering seven districts of the province. In that region, six in-depth interviews were conducted with key informants. Interviewees highlighted the increased frequency of Sandhoff genetic disease and endogamous practices (corroborated in numerous scientific results). From these data, zones of overlap of renal tumors and of Sandhoff disease were determined. Conclusions: A particular region of the province was detected with high frequency of pediatric renal tumors and Sandhoff disease. Numerous scientific studies have determined that endogamy is the risk factor that increases the frequency of Sandhoff disease in this region. In future research, it should be confirmed whether it also acts by increasing the incidence of renal tumors in children(AU)

Consanguinity and Inbreeding Coefficient F in Aligarh city, India: A Cross Sectional Study

Objective: To determine the coefficient of inbreeding of consanguinity (F) and its correlates in Aligarh city, India. Material and Methods: Cross sectional household survey with a sample size of 2000 (1600 non-consanguineous and 400 consanguineous couples) using systematic random sampling. Researcher conducted the study by visiting every tenth household of every tenth ward of Aligarh city. Information was recorded on a pre-tested questionnaire, which had questions pertaining to religion, details regarding relationship between couples (consanguineous / non consanguineous marriage), type of consanguinity (first cousin/second cousin/third cousin), level of education and occupation (a proxy for socioeconomic status). Descriptive statistics, Chi-square, and multivariate logistic regression were used. Results: Multivariate logistic regression analysis showed that Islam (p<0.001) and Christianity (p<0.001) were significantly associated with consanguinity. Private employment with (-) B value (p<0.001) showed a significant association of the variable with non-consanguineous group. Coefficient of inbreeding for the present study was 0.0538, highest reported from any part of India. Conclusion: Consanguinity is a prevailing problem in Aligarh city, India. Evidence based guidelines needed. Information ­ education ­ communication and pre-marital counseling suggested to make population aware of the consequences of consanguinity and to help couples make a decision.

Analysis of a patient with early-onset Parkinson's disease and PARK7 gene variation / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a patient with early-onset Parkinson disease from a consanguineous family.@*METHODS@#Homozygosity mapping and Sanger sequencing of cDNA were used to identify the causative mutation.@*RESULTS@#A homozygous missense variation (c.56C>G, p.Thr19Arg) in the PARK7 gene was identified in the patient. In silico analysis suggested the c.56C>G variation to be pathogenic.@*CONCLUSION@#Homozygous c.56C>G variation of the PARK7 gene was the disease-causing variation in this family.

Ophthalmological findings in ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome: a case report / Achados oftalmológicos na displasia ectodérmica, ectrodactilia e síndrome da distrofia macular: relato de caso

ABSTRACT We report on a case of two sisters, daughters of consanguineous parents, presenting with a similar condition of low visual acuity associated with retinal dystrophy in both eyes associated with alopecia and bone alterations or syndactyly.

RESUMO Relatamos um caso de duas irmãs, filhas de pais consanguíneos, apresentando uma condição semelhante de baixa acuidade visual associado à distrofia retiniana em ambos os olhos associado à alopecia e alterações ósseas ou sindactilia.

Variante patogénica homocigótica del gen BBS10 en un paciente con síndrome de Bardet-Biedl / A pathogenic homozygous variant of the BBS10 gene in a patient with Bardet Biedl syndrome

Resumen El síndrome de Bardet-Biedl es una enfermedad hereditaria, autosómica recesiva, con gran heterogeneidad de locus, que pertenece a las denominadas ciliopatías, denominadas así por la deficiencia funcional presente y porque las proteínas afectadas se localizan en el cilio primario. El síndrome afecta múltiples sistemas, con compromiso visual, renal, cognitivo, esquelético y gonadal, y obesidad. Este síndrome presenta una gran variabilidad intrafamiliar e interfamiliar. Se presenta el caso clínico de un paciente adolescente con diagnóstico de síndrome de Bardet-Biedl, así como su manejo, los resultados de la secuenciación de 22 genes y el análisis actualizado de la literatura médica. Se recopiló la información clínica y, previo consentimiento informado, se hizo la prueba de panel de secuenciación multigénica de los genes implicados. El paciente es hijo de la unión de personas consanguíneas. Fue el primer afectado en la familia y presentaba polidactilia posaxial, obesidad, micropene, retinitis pigmentaria y dificultades de aprendizaje. En el panel multigénico, se identificó la variante patogénica homocigótica c.39_46del en el gen BBS10 y otras variantes de genes BBS asociadas con la obesidad. Dado que el síndrome de Bardet-Biedl es una enfermedad huérfana rara, interpretar el pleiotropismo y la heterogeneidad de locus y de alelos, constituye un reto. La confirmación molecular permite el manejo adecuado de los pacientes, así como el seguimiento y el asesoramiento genético apropiados.

Abstract The Bardet-Biedl syndrome is an autosomal recessive hereditary disorder with vast locus heterogeneity that belongs to the so-called ciliopathies, whose proteins are localized in the primary cilia and present functional deficiency. The multisystemic features of the disease include ocular, renal, cognitive, skeletal, as well as gonadal involvement and obesity, among others, with high inter- and intrafamilial variability. We describe the clinical case of an adolescent male patient with Bardet-Biedl syndrome, including the approach, the results from a 22-gene sequencing panel, and the analysis of updated scientific literature. We collected the clinical data of the patient and, after obtaining the informed consent, we conducted a multigenic sequencing panel oriented to known implicated genes. The patient was born to consanguineous parents and was the first affected member of the family. He presented with postaxial polydactyly, obesity, micropenis, retinitis pigmentosa, and learning disability. The multigenic panel allowed the identification of the homozygous pathogenic variant c.39_46del in the BBS10 gene and in other BBS genes variants associated with obesity. As the Bardet-Biedl syndrome is a rare disease, it is challenging to interpret its pleiotropism and gene/allelic heterogeneity. Its confirmation by molecular tests allows an adequate approach, follow-up, and genetic counseling of the patient and the family.

Risk factors and comorbidities in Brazilian patients with orofacial clefts

Abstract: Considering that environmental risk factors substantially contribute to the etiology of orofacial clefts and that knowledge about the characteristics and comorbidities associated with oral clefts is fundamental to promoting better quality of life, this study aimed to describe the risk factors, main characteristics, and comorbidities of a group of patients with cleft lip and/or cleft palate (CL/P) from Rio Grande do Norte (RN), Brazil. Data were obtained from 173 patients with CL/P using a form from the Brazilian database on Orofacial Clefts. Most patients were male with cleft lip and palate and had a normal size and weight at birth; presented few neonatal intercurrent events; and had anemia and respiratory and cardiovascular diseases as main associated comorbidities. They also required timely surgical rehabilitation and multidisciplinary care to stimulate their neuropsychomotor development. In addition, a high frequency of familial recurrence and of parental consanguinity was evidenced in the studied population, especially for the cleft lip and cleft palate type. Other relevant findings were the considerable maternal exposure to alcohol, infections, smoking, and hypertension, as well as low supplementation with vitamins and minerals and deliberate consumption of analgesics, antibiotics, and antihypertensives during pregnancy. Characterization of the CL/P patient profile is essential for the planning of health services and integration among the health professionals involved in the diagnosis and treatment of these malformations. Our results reinforce the need for additional research to confirm the association between environmental factors and the development of orofacial clefts.

Associations between red reflex abnormality, consanguinity and intensive care hospitalization of newborns in Turkey

Background: Red reflex screening is the primary but unheeded test for the detection of vision- and life-threatening eye conditions.

Aims: To evaluate the red reflex of newborns, percentage of ocular diseases resulting in red reflex abnormality, and their relation with consanguinity in Southeast Turkey.

Methods: Newborns [n = 1358] were examined with pencil light and direct ophthalmoscopy.

Results: Eight hundred of these newborns were hospitalized in a rooming-in unit. [RIU] and 558 were in the neonatal intensive care service [NICS]. In the RIU there were 7 [0.88%] newborns with abnormal red reflex and in the NICS there were 14 [2.51%]. Sensitivity of pencil light examination was 71.4%. Studies from the Middle East have shown potential recessive genetic causes of common paediatric ocular conditions. In our study, consanguineous marriage was found to have a significant association with red reflex abnormality [P = 0.017].

Conclusions: Red reflex screening test is important in the early diagnosis of vision- and life-threatening eye disorders in Southeast Turkey where consanguinity is common

McArdle's disease: an underestimated or underdiagnosed myopathy in rheumatologic practice? Cases series and literature review / Doença de mcardle: uma miopatias subestimada e subdiagnosticada na pratica reumatológica? série clínica e revisão de literatura

OBJECTIVE: McArdle's disease is a metabolic myopathy that manifests with varied clinical conditions and is often confounded with other diagnoses. Herein, the authors report a case series and carry out a literature review. METHODS: A cross-sectional single-center study evaluating 12 patients with McArdle's disease was conducted. RESULTS: Mean age at onset of symptoms was 28.0±17.4 years, while age at disease diagnosis was 39.0±14.8 years. History of intolerance to physical exercises was observed in 10 cases; muscle weakness in 9, second wind phenomenon in only 1 case. The presence of cramps, fatigue and myalgia was observed in 12, 11 and 9 of the cases respectively. Median creatine phosphokinase level was 5951U/L. Most of the patients (83.3%) were initially diagnosed with another condition (polymyositis, inclusion body myositis, fibromyalgia and/or muscular dystrophy), and approximately half had received glucocorticoids and/or immunosuppressants prior to definitive diagnosis. All patients underwent muscular biopsy, which revealed the presence of subsarcolemmal vacuoles characterized by glycogen deposits, and negative histochemical reaction for the myophosphorylase enzyme. CONCLUSION: The present study reinforces the presence of clinical variability among patients and shows that McArdle's disease should be considered one of the differential diagnoses of inflammatory myopathies and other rheumatic diseases.

OBJETIVO: A doença de McArdle é uma miopatia metabólica que se manifesta com condições clínicas variadas e muitas vezes é confundida com outros diagnósticos. Os autores relatam uma série de casos e realizam uma revisão de literatura. MÉTODOS: Estudo transversal de um único centro em que foram avaliados 12 pacientes com doença de McArdle. RESULTADOS: A média de idade no início dos sintomas foi de 28,0±17,4 anos, enquanto a idade no diagnóstico da doença foi de 39,0±14,8 anos. História de intolerância ao exercício físico foi observada em 10 dos casos; fraqueza muscular em 9; fenômeno do "second wind" em apenas 1 caso. A presença de câimbras, fadiga e mialgia foi observada, respectivamente, em 12, 11 e 9 dos casos. O nível mediano de creatinafosfoquinase foi de 5951U/L. Oito pacientes foram inicialmente diagnosticados com outra condição (polimiosite, miosite de corpos de inclusão, fibromialgia e/ou distrofia muscular), e aproximadamente metade havia recebido glicocorticoides e/ou imunossupressores antes do diagnóstico definitivo. Todos os pacientes foram submetidos à biópsia muscular, que revelou a presença de vacúolos subsarcolêmicos caracterizados por depósitos de glicogênio e reação histoquímica negativa para a enzima miofosforilase. CONCLUSÕES: O presente estudo reforça a presença de variabilidade clínica entre pacientes e mostra que a doença de McArdle deve ser considerada um dos diagnósticos diferenciais de miopatias inflamatórias e outras doenças reumáticas.

Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing

SUMMARY Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS −3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene.

Prevalência de hemoglobinas variantes em comunidades quilombolas no estado do Piauí, Brasil / Prevalence of hemoglobin variants in quilombola communities in the state of Piauí, Brazil

Resumo As hemoglobinas variantes (Hb) decorrem de mutações nos genes da globina. As variantes estruturais mais frequentes são HbS, HbC, HbD e HbE. O gene da hemoglobina S tem frequência elevada na América, enquanto que no Brasil é maior no Sudeste e Nordeste. O presente artigo tem por objetivo investigar a presença de hemoglobinas variantes em 15 comunidades quilombolas do estado do Piauí. Foram analisadas 1.239 amostras, nas quais as hemoglobinas foram triadas pela cromatografia líquida de alta eficiência (HPLC). Aplicou-se questionário referente a gênero, etnia e consanguinidade das populações. Das 1.239 amostras, 5,4% apresentaram o traço falciforme AS, as doenças falciformes SS e SC apareceram em 0,8% do total, nas hemoglobinas AC, AD e DD. Das 1.069 pessoas negras, 84 apresentaram alteração das hemoglobinas; destas, 34 eram do sexo masculino e 53 do feminino. Ocorreu a presença de 13 casamentos consanguíneos dentre as 84 alterações das hemoglobinas. O estudo das hemoglobinas variantes em 15 comunidades remanescentes de quilombos do Piauí contribui para sua educação em saúde frente aos aspectos da herança genética destas proteínas, relevante questão de saúde pública, proporcionando subsídios para a implantação do Programa Estadual da Doença Falciforme do Piauí.

Abstract Hemoglobin variants (Hb) result from mutations in globin genes, with amino acid substitution in the polypeptide chain. Among the most common structural variants are HbS, HbC, HbD and HbE. The S hemoglobin gene is a high frequency gene across America and Brazil, where it is more frequent in the Southeast and Northeast. The scope of this article is to investigate the presence of hemoglobin variants in 15 quilombos (fugitive slave communities) of Piaui. The sample was of 1,239 people and hemoglobin was screened by high-performance liquid chromatography (HPLC). A questionnaire was applied related to gender, ethnicity and consanguinity. Of the samples analyzed, 5.4% had AS sickle cell trait, while SS and SC sickle cell anemia showed a rate of 0.8%, with AC, AD and DD hemoglobin. Of the 1,069 Afro-descendants, 84 revealed hemoglobin abnormalities, 34 being male 53 being female. There were 13 consanguineous marriages among the 84 hemoglobin alterations. The study of hemoglobin variants in 15 former quilombo communities in the state of Piaui contributes to their education in health in the aspects of genetic inheritance of hemoglobin, a relevant public health issue, providing input for the implementation of the State Program of Sickle Cell Disease of Piaui.