Cornelia de Lange Syndrome Caused by an Intragenic Heterozygous Deletion in RAD21 Detected through Very-High-Resolution Chromosomal Microarray Analysis.

Cornelia de Lange syndrome is a genetic and clinically heterogeneous entity, caused by at least five genes. It is characterized by short stature, gestalt facies, microcephaly, neurodevelopmental disorders, and other anomalies. In this report, we present a 13-year-old female patient with microcephaly, cleft palate, polydactyly, short stature, triangular facies, frontal bossing, a bulbous nose, an overfolded helix, limited pronosupination, and an anomalous uterus. No neurodevelopmental disorders were reported. A chromosomal microarray analysis of 6.5 million markers was performed in the proband and her parents. The results showed a de novo heterozygous microdeletion of exons 9-14 within RAD21, which confirmed the diagnosis of Cornelia de Lange syndrome type 4. Our patient did not show any neurologic phenotype (until the time of diagnosis), although neurodevelopmental disorders are frequently present in patients with Cornelia de Lange syndrome type 4, and despite carrying a deletion that was larger than previously reported. Therefore, unknown genetic modifiers or intrinsic mechanisms of RAD21 variants may exist and should be studied.

Utilidad diagnóstica de la secuenciación de segunda y tercera generación en pacientes con discapacidad intelectual: revisión rápida / Utility of second-generation sequencing and third-generation sequencing in the diagnosis of patients with intellectual disability: Rapid review

Introducción: la discapacidad intelectual se presenta hasta en el 18% de algunas poblaciones. Las causas son variantes genéticas puntuales y variantes en el número de copias detectadas por la secuenciación de segunda generación y el análisis cromosómico por micromatrices, respectivamente. Sin embargo, se tiene otras variantes, como las estructurales, repetición de trinucleótidos o trastornos de la impronta que solo son detectadas por otras pruebas específicas. La secuenciación de tercera generación tiene el potencial de detectar todas las variantes genéticas. El objetivo es determinar las ventajas de la secuenciación de tercera generación sobre la de segunda generación en pacientes con discapacidad intelectual. Material y métodos: búsqueda sistemática mediante los tesauros MESH «discapacidad intelectual» y «secuenciación de segunda generación»; así como el término de «secuenciación de tercera generación». Resultados: se seleccionaron 31 artículos; 9 utilizaron la secuenciación de tercera generación en pacientes con estudios genómicos previos y se encontró que el 40% tenían variantes estructurales. Los que emplearon la secuenciación de segunda generación (n = 22) determinaron mediante un metaanálisis, que detectaron variantes de un solo nucleótido y variantes en el número de copias en un 29,8 y 9,2% de los casos, respectivamente. Conclusiones: la secuenciación de tercera generación tiene la capacidad de encontrar variantes estructurales, disomías uniparentales, repetición de trinucleótidos y variantes de un solo nucleótido, lo cual permitiría tener una mayor probabilidad de establecer la etiología de la discapacidad intelectual. Sin embargo, se necesitan estudios con muestras más representativas no solo en quienes padecen de discapacidad intelectual, sino a nivel poblacional.(AU)

Introduction: Some populations have an intellectual disability frequency of nearly 18%. Among, the diverse genetic causes are single nucleotide variants and copy number variations, detected with second-generation sequencing and chromosomal microarray analysis, respectively. Nevertheless, other variants such as structural variants, trinucleotide repeat or imprinting disorders, cannot be detected by these tests and require different specific techniques. Third-generation sequencing have a power of found all variants. The purpose is to stablish the benefits of using third generation sequencing above second-generation sequencing in the diagnosis of patient with intellectual disability. Material and methods: A rapid systematic review was performed on the Medline using thesaurus terms MESH of “intellectual disability” and “second-generation sequencing”; as well as using the term “third-generation sequencing”. Results: 31 articles were selected in total. Of those, nine used third-generation sequencing in patients with previously genomic test, and founded structural variants in 40% of cases, all these variants were corroborated with other gold standard tests. Twenty-two studies used second-generation sequencing (n = 22) and showed through metanalysis, that 29,8% and 9,2% of these cases are due a single nucleotide variant and copy number variations, respectively. Conclusions: Third-generation sequencing can find structural variants, uniparental disomies, trinucleotide repeat and single nucleotide variation. Therefore, it would allow a broader and better study of the etiology of intellectual disability. Nevertheless, more research with larger representative samples in patients and healthy population is needed.(AU)

Enfermedad ultrarara frecuente en Perú: Reporte de casos del síndrome FATCO

El síndrome FATCO (fibular aplasia, tibial camptomelia, oligosyndactyly) está caracterizado por la presencia de anomalías en miembros inferiores. Es una enfermedad, de la cual no se ha precisado la etiología genética hasta la actualidad; sin embargo, se ha planteado que el tipo de herencia es dominante autosómica. La frecuencia de presentación a nivel global es muy rara y esta es la razón principal de los pocos pacientes publicados hasta la fecha. Existe un reporte de la presentación inusual de catorce pacientes peruanos, diagnosticados en un solo centro, con las características clínicas del síndrome FATCO en un período de 13 años. A la fecha, se han publicado catorce pacientes a nivel mundial, con los cuales se comparó y discutió los datos clínicos y radiológicos. Además, se analizaron las características demográficas, antecedentes familiares, sexo, edad y anomalías concomitantes.

The fibular aplasia, tibial campomelia, oligosyndactyly (FATCO) syndrome is characterized by the variable leg anomalies. The genetic etiology of this disease has not been determined to date; however, it has been suggested that the genetic inheritance is autosomal dominant. The frequency of presentation globally is infrequent and this is the main reason for the low number of patient reports. There's a report of the unusually high presentation of 14 peruvian patients diagnosed at a single center with the clinical features of FATCO syndrome over a 13-year period. We compare and discuss the clinical and radiological data of our patients with those of the 14 cases described worldwide. In addition, the demographic characteristics, family history, sex, age, and concomitant anomalies are analyzed.

Peruvian Newborn Male with 3p13 Deletion Syndrome Encompassing the FOXP1 Gene: Review of the Literature.

Copy number variation in loss of 3p13 is an infrequently reported entity characterized by hypertelorism, aniridia, microphthalmia, high palate, neurosensorial deafness, camptodactyly, heart malformation, development delay, autism spectrum disorder, seizures, and choanal atresia. The entity is caused probably by haploinsufficiency for FOXP1, UBA3, FAM19A1, and MITF. We report a newborn male with hypotonia, facial dysmorphism, heart malformation, and without clinical diagnosis; nevertheless, the use of appropriate genetic test, such us the chromosomal microarray analysis allowed identification of a copy number variant in loss of 5.5 Mb at chromosome 3 (p13-p14.1), that included 54 genes, encompassing FOXP1 gene. We compare the findings in our Peruvian patient to those of earlier reported patients; furthermore, add new signs for this entity.

Variantes en el número de copias en trastornos del neurodesarrollo, síndrome malformativo y talla baja en Perú / Copy number variation in development disorders, malformative syndrome and short stature in Peru

RESUMEN Objetivo : determinar las variantes en el número de copias y regiones de homocigosidad mediante el análisis cromosómico por micromatrices, en niños con diagnóstico de trastorno del neurodesarrollo: retraso del desarrollo psicomotor (RDPM), discapacidad intelectual (DI) y trastorno del espectro autista (TEA), así como pacientes con síndrome malformativo (SM) y talla baja idiopática (TBI). Materiales y métodos : se evaluaron a 367 niños peruanos diagnosticados clínicamente con DI, RDPM, TEA, TBI y SM a quienes se les realizó el análisis cromosómico por micromatrices (CMA 750K CGH+SNP) en sangre periférica, entre los años 2016-2018. Resultados : las edades fluctuaron entre los 4,8 meses y los 18 años, con una media de 5,6 años. Los diagnósticos más frecuentes fueron RDPM (48%) y DI (30%). Se reportaron resultados anormales (variantes patogénicas, probablemente patogénicas, disomías uniparentales y regiones de homocigosidad superiores a 2,56%) en el 50,3% de los pacientes. Los resultados anormales se observaron en el 53,3% de los casos con diagnóstico de DI y el 47,9% de RDPM; mientras que en el resto de los casos con TBI sindrómica, SM y TEA tuvieron resultados anormales en el 52,4%, 52% y 20% respectivamente. Por otro lado, encontramos hasta un 6,2% de los padres eran consanguíneos no declarados. Conclusiones : la tasa de detección de las variantes en el número de copias (CNVs) encontrada en nuestro estudio fue superior a la reportada en estudios internacionales independientemente del diagnóstico clínico. Además, se pudo encontrar una mayor frecuencia de consanguinidad no declarada con relación a estudios anteriores.

ABSTRACT Objective: To establish the ratios of the copy number variations and regions of homozygosity through chromosomal microarray analysis (CMA) in children with neurodevelopmental disorders: development delay (DD), intellectual disability (ID), and/or autistic spectrum disorder (ASD), malformative syndrome (MS) and idiopathic short stature (ISS). Materials and Methods: We evaluated 367 Peruvian children diagnosed clinically with ID, DD, ASD, ISS and MS to whom performed chromosomal microarray analysis in peripheral blood (750K CGH + SNP), between the years 2016-2018. Results: Patients' age fluctuated between 4.8 months and 18 years old, with an average of 5.6 years old. The most frequent diagnoses were development delay (48%) and intellectual disability (30%). Abnormal results (pathogenic variants, likely pathogenic variants, uniparental disomies and loss of heterozygosity> 2.5%) were reported in 50.3%. The 53.28% of the cases with a diagnosis of intellectual disability and 47.92% of development delay showed abnormal results; while the children with short stature syndromic, malformative syndrome, and autistic disorders spectrum disorders showed abnormal results in 52.38%, 52% and 20% respectively. Additionally, we found that 6.25% of parents were non-declared consanguinity. Conclusions: Abnormal results found in our study was a higher ratio than other international reports regardless of the clinical diagnosis. Furthermore, we show a most rate of non-declared consanguinity in relation with previous reports.

A novel ASPH variant extends the phenotype of Shawaf-Traboulsi syndrome.

Shawaf-Traboulsi syndrome (or Traboulsi syndrome; MIM 601552) is an infrequently reported entity characterized by a typical face (long face, large nose, convex nasal ridge, underdeveloped malae, crowded teeth, retrognathia), skeletal signs (long and slender fingers, sometimes pectus deformation and hypermobile joints), and ectopia lentis with conjunctival blebs, shallow anterior chamber and iridocorneal adhesions. The entity is caused by homozygous variants in ASPH. Here, we report on a boy with the clinical diagnosis of Shawaf-Traboulsi syndrome, in whom exome sequencing allowed identification of a novel variant in ASPH. We compare the findings in the present patient to those of earlier reported patients; furthermore add new signs for this entity.

Factores de riesgo en las enfermedades genéticas / Risk factors in genetic diseases

Existen más de 10 000 enfermedades genéticas descritas en el mundo y afectan alrededor del 7% de la población mundial, causando alta morbimortalidad y costos para los sistemas de salud pública. Representan un reto diagnóstico por la variabilidad clínica y la necesidad de pruebas diagnósticas moleculares. En el Perú, son escasas las investigaciones respecto a estas condiciones y, aunque se ha promulgado la Ley de Enfermedades Huérfanas o Raras (Ley Nº 29698), no se han implementado estrategias sanitarias nacionales para el diagnóstico, manejo y prevención. La presente publicación tiene como objetivo describir los factores de riesgo más frecuentes, los cuales están relacionados a enfermedades o síndromes de etiología genética

More than 10,000 genetic diseases have been described, which affect approximately 7% of the whole world population, leading to high morbidity and mortality rates, as well as to elevated healthcare costs. The diagnosis of these conditions is a tough challenge, because of their clinical variability and the low availability of molecular diagnostic tests. There is little research performed in Peru dealing with these diseases, and although a 'Bill for Orphan or Rare Diseases' (Law N° 29698) has been recently issued, no national healthcare strategies have been implemented for the diagnosis, management, and prevention of genetic diseases. This paper aims to describe the risk factors that are more frequently related to diseases or syndromes with a genetic origin

Noonan syndrome in diverse populations.

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely spaced eyes and low-set ears in 80% or greater of participants, short stature in more than 70%, and pulmonary stenosis in roughly half of study individuals. Using facial analysis technology, we compared 161 Caucasian, African, Asian, and Latin American individuals with NS with 161 gender and age matched controls and found that sensitivity was equal to or greater than 94% for all groups, and specificity was equal to or greater than 90%. In summary, we present consistent clinical findings from global populations with NS and additionally demonstrate how facial analysis technology can support clinicians in making accurate NS diagnoses. This work will assist in earlier detection and in increasing recognition of NS throughout the world.