Genetic analysis of a Chinese pedigree with 6q26q27 microduplication and 15q26.3 microdeletion / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree with 6q26q27 microduplication and 15q26.3 microdeletion.@*METHODS@#A fetus with a 6q26q27 microduplication and a 15q26.3 microdeletion diagnosed at the First Affiliated Hospital of Wenzhou Medical University in January 2021 and members of its pedigree were selected as the study subject. Clinical data of the fetus was collected. The fetus and its parents were analyzed by G-banding karyotyping and chromosomal microarray analysis (CMA), and its maternal grandparents were also subjected to G-banding karyotype analysis.@*RESULTS@#Prenatal ultrasound had indicated intrauterine growth retardation of the fetus, though no karyotypic abnormality was found with the amniotic fluid sample and blood samples from its pedigree members. CMA revealed that the fetus has carried a 6.6 Mb microduplication in 6q26q27 and a 1.9 Mb microdeletion in 15q26.3, and his mother also carried a 6.49 duplication and a 1.867 deletion in the same region. No anomaly was found with its father.@*CONCLUSION@#The 6q26q27 microduplication and 15q26.3 microdeletion probably underlay the intrauterine growth retardation in this fetus.

Study of a fetus with confined placental mosaicism for trisomy 2 in conjunct with fetal uniparental disomy and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To carry out genetic analysis for a fetus with confined placental mosaicism (CPM) for trisomy 2 (T2) in conjunct with fetal uniparental disomy (UPD).@*METHODS@#Amniocentesis and chromosomal karyotyping was carried out for a pregnant woman with a high risk for chromosome 2 anomalies indicated by non-invasive prenatal testing (NIPT). Single nucleotide polymorphism array (SNP-array) and trio-whole exome sequencing (Trio-WES) were carried out. Ultrasonography was used to closely monitor the fetal growth. Multifocal sampling of the placenta was performed after delivery for copy number variation sequencing (CNV-seq).@*RESULTS@#The fetus was found to have a normal chromosomal karyotype. SNP-array has revealed multiple regions with loss of heterozygosity (LOH) on chromosome 2. Trio-WES confirmed the presence of maternal UPD for chromosome 2. Ultrasonography has revealed intrauterine growth restriction and oligohydramnios. Intrauterine fetal demise had occurred at 23+4 weeks of gestation. Pathological examination had failed to find salient visceral abnormality. The placenta was proved to contain complete T2 by CNV-seq.@*CONCLUSION@#T2 CPM can cause false positive result for NIPT and may be complicated with fetal UPD, leading to adverse obstetric outcomes such as intrauterine growth restriction, oligohydramnios and intrauterine fetal demise.

Study on clinical features and diagnostic methods of prenatal Wolf-Hirschhorn syndrome / 中华医学遗传学杂志

OBJECTIVE@#To investigate the clinical features of fetuses with Wolf-Hirschhorn syndrome(WHS) and explore the diagnostic methods and prenatal ultrasound characteristics and provide evidence for prenatal genetic counseling.@*METHODS@#We retrospectively analyzed 5 cases of WHS fetuses diagnosed from March 2016 to February 2020, and analyzed the results of chromosomal karyotype analysis and chromosomal microarray analysis (CMA) of the fetuses.@*RESULTS@#Five cases of WHS were detected by CMA, four cases were detected by karyotype analysis. Prenatal ultrasound revealed 4 abnormalities, of which 3 had intrauterine growth restriction, and only 1 had abnormalities of the maxillofacial region. The sequence of the fragments was 4p16.3p16.1 with a loss of 6.5 Mb, 4p16.3p15.32 with a loss of 15.6 Mb combined with 2p25.3 increased by 906kb, 4p16.3p15.31 with a loss of 20.4 Mb, 4p16.p15.1 with a loss of 35 Mb and 4p16.3p14 with a loss of 37 Mb.@*CONCLUSION@#Fetal growth restriction may be one of the early manifestations of WHS. Absence of fetal facial abnormality by prenatal ultrasound screening cannot exclude WHS. Karyotype analysis may miss the diagnosis of WHS, while combined CMA techniques can improve the diagnostic accuracy.

Effects of FTO and PPARγ variants on intrauterine growth restriction in a Brazilian birth cohort

Intrauterine growth restriction (IUGR) is related to a higher risk of neonatal mortality, minor cognitive deficit, metabolic syndrome, and cardiovascular disease in adulthood. In previous studies, genetic variants in the FTO (fat mass and obesity-associated) and PPARγ (peroxisome proliferator-activated receptor-gamma) genes have been associated with metabolic disease, body mass index, and obesity among other outcomes. We studied the association of selected FTO (rs1421085, rs55682395, rs17817449, rs8043757, rs9926289, and rs9939609) and PPARγ (rs10865710, rs17036263, rs35206526, rs1801282, rs28763894, rs41516544, rs62243567, rs3856806, and rs1805151) single-nucleotide polymorphisms (SNPs) with IUGR, through a case-control study in a cohort of live births that occurred from June 1978 to May 1979 in a Brazilian city. We selected 280 IUGR cases and 256 controls for analysis. Logistic regression was used to jointly analyze the SNPs as well as factors such as maternal smoking, age, and schooling. We found that the PPARγ rs41516544 increased the risk of IUGR for male offspring (OR 27.83, 95%CI 3.65-212.32) as well as for female offspring (OR=8.94, 95%CI: 1.96-40.88). The FTO rs9939609 TA genotype resulted in a reduced susceptibility to IUGR for male offspring only (OR=0.47, 95%CI: 0.26-0.86). In conclusion, we demonstrated that PPARγ SNP had a positive effect and FTO SNP had a negative effect on IUGR occurrence, and these effects were gender-specific.

Un caso de deleción parcial 1p36. 1 y trisomía parcial 6p diagnosticadas por cariotipo / A case of partial 1p36. 1 deletion and partial trisomy 6p diagnosed by karyotype

La deleción de la región cromosómica 1p36 es una de las anomalías subteloméricas más frecuentes y causa rasgos dismórficos distintivos. Por otro lado, la trisomía distal del brazo corto del cromosoma 6 es una anormalidad cromosómica poco frecuente de fenotipo variable. Objetivo: Presentar el caso de un paciente con ambas alteraciones cromosómicas, y resaltar la vigencia e importancia del cariotipo como herramienta diagnóstica en dismorfología. Caso clínico: Lactante de 2 meses de edad con múltiples anomalías craneofaciales, hemangioma en la nuca, fosita sacra, acortamiento rizomélico, pies y manos pequeños, criptorquidia unilateral izquierda e hipotonía. Además, antecedente de restricción del crecimiento intrauterino. Producto del octavo embarazo de una mujer G8A7C1 de 28 años. Con estos hallazgos inespecíficos en el fenotipo se solicitó cariotipo que mostró una deleción parcial de 1p36.1 y una trisomía parcial de cromosoma 6p. Conclusión: El cariotipo convencional sigue siendo una herramienta importante para el etiológico en pacientes con anomalías congénitas (múltiples), mostrando en este caso una deleción parcial de 1p36.1 y una trisomía parcial de cromosoma 6p, alteraciones cromosómicas estructurales.

The deletion of chromosomal region 1p36 is one of the most common sub-telomeric microdeletion syndromes and has distinctive dysmorphic features. On the other hand, partial trisomy of the short arm of chromosome 6 is a rare chromosomal abnormality with a variable phenotype. Objective: To report a case with both chromosome abnormalities, and to highlight the importance of the karyotype as a diagnostic tool in dysmorphology. Clinical case: The case of is presented of a two month-old infant with several craniofacial anomalies, neck haemangioma, sacral pit, rhizomelic shortening, small hands and feet, left unilateral cryptorchidism, and hypotonia. The infant also suffered intrauterine growth restriction and is the product of the eighth pregnancy of a 28 years old woman. Due to the unspecific findings in phenotype, a karyotype was requested, which showed a partial deletion of 1p36.1 and a partial trisomy of chromosome 6. Conclusion: The development of new techniques in molecular biology has improved diagnostic possibilities in medical genetics. However, the traditional karyotype remains as an important diagnostic tool in patients with multiple congenital anomalies.

Variações no número de cópias cromossômicas submicroscópicas como causa de baixa estatura de início pré-natal / Submicroscopic chromosomal copy number variants as a cause of prenatal onset short stature

A pesquisa de variações no número de cópias (CNVs; copy number variants) cromossômicas tem revelado o importante papel destas alterações genômicas na diversidade populacional e na etiologia de doenças humanas. O modelo de associação de CNVs a doenças envolve deleções e/ou duplicações individualmente raras, mas com segmentos cromossômicos de tamanhos relevantes. Os pacientes com baixa estatura de início pré-natal constituem um grupo heterogêneo com quadros clínicos complexos frequentemente resultantes de alterações genéticas, que, desde o período intrauterino, perturbam os mecanismos e vias de desenvolvimento e crescimento fetais. Assim sendo, aventamos a hipótese de que CNVs raras possam estar entre as causas genéticas de baixa estatura de início prénatal. Para tanto, nosso estudo visou avaliar a presença de deleções ou duplicações submicroscópicas em um grupo selecionado de pacientes nascidos pequenos para idade gestacional (PIG) com baixa estatura persistente sem causa definida. Foram avaliados 51 pacientes nascidos PIG com baixa estatura persistente após o 4º ano de vida que apresentavam dismorfismos, atraso de desenvolvimento neuropsicomotor (DNPM) ou deficiência intelectual, porém sem caracterizar síndromes conhecidas e com cariótipo normal. Amostras de DNA dos pacientes foram submetidas à hibridização genômica comparativa por microarray (aCGH; array comparative genomic hybridization) baseada em oligonucleotídeos na plataforma 60K. Os achados foram comparados com CNVs descritas em bancos de dados de controles normais. Foram identificadas 18 CNVs, ausentes em controles saudáveis, em 17 dos 51 pacientes (33%). As alterações foram avaliadas para classificação de sua patogenicidade de acordo com os seguintes critérios: 1) padrão de herança e segregação familiar; 2) sobreposição a coordenadas genômicas de síndromes conhecidas; 3) sobreposição a CNVs patogênicas descritas em banco de dados; 4) e conteúdo gênico. Quatro CNVs, encontradas em 3 pacientes, foram...

Analysis of chromosomic copy number variants (CNVs) have demonstrated the important role of these genomic imbalances in population diversity and human disease. The model of CNV disease association involves deletions and/or duplications that are individually rare but encompass chromosomal segments of relevant size. Prenatal onset short stature patients constitute a complex group characterized by clinical heterogeneity. The causes of prenatal growth impairment frequently involve genetic changes that disturb the mechanisms and the pathways of fetal growth and development. Thus, we hipothesized that rare CNVs might contribute to the genetic etiology of prenatal onset short stature. In order to evaluate this assumption, our study analyzed the presence of submicroscopic deletions and/or duplications in a selected group of patients born small for gestational age with persistent short stature but without a recognized cause. A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features, developmental delay and/or intellectual disability, but without criteria for known syndromes, were selected. All patients had normal G-banded karyotyping. Array-based comparative genomic hybridization (aCGH) in a whole-genome 60K platform was performed using DNA obtained from all patients. Detected CNVs were compared with CNV data from healthy controls individuals, excluding common copy number polymorphisms. In 17 of the 51 patients screened (33%), 18 rare CNVs were identified. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance and familial segregation; overlap with genomic coordinates for a known genomic imbalance syndrome; overlap with CNVs previously identified in other patients with prenatal onset short stature; and gene content. Four distinct CNVs, found in three patients, were classified as pathogenic: 1) del 22q11.21; 2) dup 10q26.2-26.3 and del 10q26.3; and 3) del 4q28.2-q31.21. Five CNVs, found...

Mutações no gene do receptor do fator de crescimento insulina-símile 1 (IGF1R) como causa de retardo do crescimento pré- e pós-natal / Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation

Aproximadamente 10 por cento das crianças nascidas pequenas para a idade gestacional (PIGs) não apresentam recuperação espontânea do crescimento. As causas desse déficit de crescimento pré-natal e sua manutenção após o nascimento ainda não são completamente conhecidas na maioria dos casos. Nos últimos oito anos, diversas mutações inativadoras e deleções do gene IGF1R em heterozigose foram relatadas, indicando o papel de defeitos no eixo IGFs/IGF1R como causa do déficit de crescimento. Postula-se que pelo menos 2,5 por cento das crianças nascidas PIGs possam apresentar defeitos no gene IGF1R. O quadro clínico desses pacientes apresenta grande variabilidade quanto à gravidade do retardo de crescimento e aos parâmetros hormonais. Nos casos mais evidentes, os pacientes apresentam microcefalia, déficit cognitivo leve e valores elevados de IGF-1, associados à baixa estatura de início pré-natal. Esta revisão abordará os aspectos clínicos, moleculares e do tratamento da baixa estatura com hrGH de crianças com mutações no IGF1R.

Approximately 10 percent of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5 percent of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene.

Estudo do gene do fator de crescimento insulina-símile 1 (IGF1) e de receptor (IGF1R) em crianças nascidas pequenas para a idade gestacional / Study of insuline-like growth factor gene (IGF1) and its receptor in children born small for gestational age

Crianças nascidas pequenas para a idade gestacional (PIG) apresentam maior risco de permanecerem com baixa estatura na vida adulta. Os fatores de crescimento insulina-símile 1 e 2 (IGF-1 e IGF-2) são os principais fatores endócrinos determinantes do crescimento fetal. Na vida pós-natal o GH, principal hormônio promotor de crescimento, exerce a maior parte de seus efeitos por meio do IGF-1. A grande maioria das ações conhecidas do IGF-1 e IGF-2 são mediadas via receptor tirosina quinase conhecido como receptor tipo 1 de IGFs (IGF-1R). Os objetivos deste trabalho foram estudar os genes IGF1 e IGF1R em crianças nascidas pequenas para a idade gestacional que não recuperaram o crescimento na vida pós-natal. Foram selecionados 145 pacientes nascidos PIG, 72 sem catch up e 73 com catch up. Em 54 PIG sem catch up foi estudado toda a seqüência codificadora do gene IGF1 por meio de PCR e seqüenciamento direto, nos demais PIG sem catch up e nos 73 PIG com catch up foi estudado apenas o exon 6 do IGF-1 por PCR e seqüenciamento direto para avaliação de um polimorfismo encontrado nesta região. Nos pacientes que apresentavam concentração sérica de IGF-1 e IGFBP-3 acima da média para idade e sexo e seqüência do IGF1 normal (n=23) foi realizada coleta de sangue periférico com posterior separação de leucócitos mononucleares pelo gradiente de ficoll seguido por extração de RNA pelo método de Trizol® Posteriormente, a partir do RNA, sintetizamos o cDNA (DNA complementar) utilizando primers randômicos. Foi realizado PCR e seqüenciamento direto do cDNA, além de análise da expressão do IGF1R por PCR em tempo real. Nenhuma mutação foi encontrada no gene IGF1. Entretanto um locus altamente polimórfico foi encontrada na região 3' não traduzida do exon 6 deste gene, região esta envolvida no processo de poliadenilação. A freqüência das variantes alélicas foi semelhante em PIG com e sem catch-up e em controles nascidos AIG. Analisando o fenótipo de pacientes PIG...

Children born small for gestational age (SGA) have a higher risk of remaining short in adulthood. The insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) are the main factors determining endocrine fetal growth. GH is the main promoter of linear growth in the postnatal life, exerting its effects mostly through the IGF-1. The vast majority of known actions of IGF-1 and IGF-2 are mediated by the insulin-like growth factor type 1 receptor (IGF-1R), a member of the tyrosine kinase receptors family. The aim of this study was to investigate IGF1 and IGF1R genes mutations in children born small for gestational age without catch up growth in postnatal life. We selected 145 patients born SGA, 72 without catch-up and 73 with catch up. The whole coding region of the IGF1 gene was sequenced in 54 patients without catchup. In the other SGA children without catch-up and in 73 SGA with catch-up, only the exon 6 of IGF1 was sequenced to assess the influence of allelic variants present in this region. In patients with normal IGF1 sequence and IGF-1 and IGFBP-3 serum levels above the mean for age and sex (n = 23) total RNA was extracted from peripheral blood lymphocytes followed by cDNA synthesis with random primers. The IGF1R cDNA was amplified using specific primers followed by direct sequencing. IGF1R expression was analyzed by real-time PCR. No mutations were found in the IGF1 gene. However a highly polymorphic sequence was identified in the upstream core polyadenylation signal (UCPAS) located in IGF1 3' UTR at exon 6. The frequency of the identified allelic variants was similar in SGA children with and without catch-up and in controls. Furthermore, children homozygous for the wild-type allele and those carrying the allelic variants in homozygous or heterozygous state presented similar weight and length at birth, as well as serum IGF-1 levels and postnatal growth features. Two novel nonconservative allelic variants were identified in IGF1R in 23 SGA children...

Galloway-Mowat syndrome

Galloway-Mowat syndrome is a rare multisystem genetic disorder with constellation of neurological, skeletal, growth, facial, gastrointestinal and renal abnormalities. This case report describes Galloway-Mowat syndrome in a young boy suffering from congenital microcephaly, developmental delay, seizures and various dysmorphic features in whom nephritic syndrome became apparent at 5 years of age

Association between maternal-fetal genetic histocompatibility and maternal undernutrition in mice: influence on intrauterine growth

OBJETIVO: Avaliar os efeitos da histocompatibilidade genética materno-fetal e sua associação com a desnutrição materna em relação ao crescimento fetal e número de fetos. MÉTODOS: Fetos singênicos ou alogênicos em relação às respectivas mães foram obtidos através de cruzamentos de camundongos com linhagens genéticas bem definidas (A/J e Balb/c). As fêmeas grávidas foram alimentadas ad libitum com dieta normal contendo 22% de proteínas ou dieta com restrição, contendo 14% de proteína e aporte máximo de 70% do total consumido pelo grupo em dieta livre. No final da gestação, o número de unidades feto-placentárias e de perdas fetais, o peso da placenta e do feto, assim como o peso do cérebro e do fígado foram anotados. RESULTADOS: Os fetos das mães submetidas à desnutrição mostraram redução no peso corpóreo, placentário e cerebral (p<0.01), sendo que a associação entre a compatibilidade genética materno-fetal resultou em maior restrição ao crescimento fetal (p<0.01). Foi observada uma redução no número de fetos viáveis por fêmea entre os animais do grupo de restrição nutricional (p<0.01). Embora a ocorrência de compatibilidade genética materno-fetal tenha resultado na redução do número de fetos viáveis e numa tendência ao aumento de perdas fetais, esta diferença não foi significante. CONCLUSÕES: Em camundongos, a ocorrência de histocompatibilidade genética materno-fetal não modificou o crescimento fetal; a desnutrição materna durante a gestação resultou em retardo de crescimento fetal com menor tamanho da ninhada, e a associação dos dois fatores aumentou a redução do peso fetal.

Sanjad Sakati syndrome [HRD syndrome]

We are reporting two cases with HRD or Sanjad Sakati syndrome from European Gaza Hospital in southern region of Gaza strip - Palestine. They are one boy and one girl from two different families and their parents are consanguineous giving evidence of autosomal recessive inheritance pattern. Both cases are presented with severe hypocalcemic seizures, severe growth retardation and dysmorphic features. Both of them have low parathyroid hormone and renal nephrocalcinosis. None of them has significant cardiac lesion or medullary stenosis in the long bones. Genetic test was not done in both of them because lack of facilities

Síndrome de seckel: a propósito de un caso: Centro de Recuperación Nutricional Infantil "Dr. Pastor Oropeza "San Cristobal Estado Táchira Venezuela noviembre 2004 / Syndrome of seckel: a purpose of a case: Centro de Recuperacion Nutricional Infantil Dr. Pastor Oropeza San Cristóbal state Táchira noviembre 2004

El Síndrome de Seckel es una enfermedad congénita, un trastorno autosónico recesivo y la forma más frecuente de enanismo osteodisplásico microcefálico. Fue descrita por primera vez como "enanismo de cabeza de pájaro" por Rudolf Virchow en 1982, posteriormente en 1960 Helmut Seckel caracterizó el síndrome tal como conocemos en la actualidad (1), con retraso del crecimiento intrauterino, microcefalia, dwarfismo (forma de enanismo proporcionado), y facie peculiar (4).

Intrauterine growth restriction: a perspective for Pakistan

Intrauterine growth restriction [IUGR] is the second leading contributor to the prevailing perinatal mortality and morbidity. It affects 23.8% of newborns around the world and 75% of these affected infants are born in Asia. In Pakistan the incidence of IUGR is around 25%, more than the WHO criteria for triggering a public health action. IUGR is implicated with profound long-term impacts in adult life; like coronary heart disease, NIDDM and abnormal cortisol levels. The effects of the short and long term sequelae are reviewed. IUGR is associated with a wide variety of etiological factors. But the factor unique in its importance to Pakistan is maternal malnutrition. The fetal gene expression is under the influence of nutrition. Growth projection curves showing the interaction between the genetic and environmental factors are discussed. Identification of IUGR baby in a primary care setting and the options in diagnosis in secondary and tertiary care settings are overviewed. The roots of this problem, with multi factorial causes are in the socioeconomic infrastructure. This calls for a synergistic approach of reducing this public health issue. Women empowerment can help us to get out of this intergenerational cycle of growth failure. Availability of resources aside, it is also a matter of political will to change things for the better

Partial trisomy of chromosome 10 inherited from a carrier father.

Partial trisomy of chromosome 10q is a very rare condition with only four cases having been reported int he literature. This report describes a neonate with symmetric growth retardation and multiple dysmorphic features, in whom G-banded chromosomal analysis revealed a partial trisomy of chromosome 10q (q2.4-q ter). The father was diagnosed as a carrier of a balanced translocation with a karyotype of 46, XY t(10.3) (q2.4L : pter). In patients with a bad obstetric history, genetic counselling prior to a new conception cna aid in early prenatal diagnosis of fetuses with recurrent chromosomal abnormalities by means of fetal tissue sampling.

Diagnóstico antenatal doi crescimento intra-uterino retardado / Antenatal diagnosis of fetal growth retardation

Apesar dos atuais avanços propedêuticos, persistemm as dificuldades do diagnóstico antenatal do crescimento intra-uterino retardado. Em nossa casuística, observamos que esta identificaçåo foi tardia, realizada mais assiduamente no período pós-natal. Em apenas 48,8 por cento das gestantes seguidas no pré-natal da Escola Paulista de Medicina, o reconhecimento do agravo fetal ocorreu antes do nascimento. O diagnóstico antenatal foi ainda menos eficiente naquelas pacientes oriundas de outros serviços (31,1 por cento) e nas que nåo realizaram acompanhamento pré-natal (12,5 por cento). Em 60,7 por cento das vezes, a resoluçåo da gravidez ocorreu na mesma semana em que foi efetuado o diagnóstico de CIUR

Sindrome de Dubowitz: presentación de un caso / The Dubowitz syndrome: a case report

Se presenta un paciente masculino de 4 años 11 meses de edad con el síndrome de Dubowitz. La enfermedad sigue herencia autosómica recesiva y es una de las causas genéticas de retardo en el crecimiento intrauterino y talla baja postnatal. Se acompaña de microcefalia, frente inclincada, puente nasal ancho, telecanto, ptosis palpebral o blefarofimosis, epicanto bilateral, micrognatismo, paladar ojival y pabellones auriculares displásicos y prominentes