Clinical and Genetic Profile of Children With Short Stature Presenting to a Genetic Clinic in Northern India

Objective: To define the spectrum of genetic disorders in patients with short stature visiting the genetic out-patient department in a tertiary care hospital. Methods: A chart review was done for 455 individuals (10 months-16 yrs) with short stature, who were evaluated at the genetic clinic from 1 January, 2017 upto 31 October, 2018. 226 patients who needed detailed evaluation, the spectrum of genetic diagnosis is presented. Results: Proportionate short stature was identified in 63% individuals (n=142) of which 93 (65%) were recognizable syndromes such as Turner syndrome, and William syndrome, and RASopathies. In clinically undefined syndromes (39, 27%), a diagnosis could be made by karyotype (n=3/10), chromosomal microarray (6/12) and exome sequencing (1/6). In the 84 children in the disproportionate short stature group (37%), lysosomal storage disorders (LSDs) (45%, n=38) were identified by enzyme analysis in 86.8% and skeletal dysplasias (44%, n=37) identified by skeletal survey in 89% cases. Conclusions: In undefined syndromic short stature, chromosomal microarray may be the first investigation of choice if phenotyping is not suggestive of a specific genetic syndrome. Exome sequencing can be useful in identifying newer genes among idiopathic and familial short stature cohorts.

Outcomes of Very Preterm Neonates Born by Assisted Reproductive Techniques (ART): A Propensity Score Matched Retrospective Cohort Study

Objective: To compare outcomes of preterm neonates born through assisted reproduction techniques (ART) and non-ART conception. Methods: This retrospective cohort study included very preterm neonates (26 weeks to 31 weeks) admitted to our neonatal unit over a six year period from 2014 to 2019. The primary outcome was composite adverse outcome of mortality or any of the major morbidities i.e., intraventricular hemorrhage (IVH) grade ?3, periventricular leukomalacia (PVL) grade ?2, bronchopulmonary dysplasia (BPD) at 36 weeks, and retinopathy of prematurity (ROP) requiring treatment. Results: Total of 759 neonates (253 in ART group, 506 in non-ART group) were included after propensity score matching for gestational age, sex, and small for gestational age (SGA). Neonates in ART group had similar rates of composite adverse outcome [aOR (95% CI) 0.86 (0.55 – 1.36)], mortality [0.93, (0.53- 1.64)] BPD [1.18, (0.37 – 3.76)]; ROP requiring treatment [ 0.49 (0.14-1.71], and other morbidities. Conclusion: Very preterm neonates born through ART were not at increased risk of adverse neonatal outcomes.

Phenotype analysis of 11 fetuses with 22q11.2 microduplication diagnosed prenatally / 中华全科医师杂志

Objective:To analyze the clinical phynotypes of fetuses with 22q11.2 microduplications.Method:Eleven fetuses were diagnosed with 22q11.2 microduplications among 2 969 cases who underwent prenatal chromosomal microarray analysis from January 2016 to February 2020. The phenotypes, indications for invasive prenatal diagnosis, genetic results, pregnancy outcomes and postnatal clinical presentation were analyzed.Results:There were 6 cases diagnosed with classic 3.0 Mb microduplication (DiGeorge and velocardiofacial syndromes, DGS/VCFS) in the 22q11.2, 1 case with 1.5 Mb proximal microduplication and 4 cases with distal small segment microduplication (E-H). Out of 11 fetuses with 22q11.2 microduplications,7 cases were inherited, 2 cases was de novo and data were not available for 2 cases. Vicular septal defect and anencephalu were diagnosed by ultrasonography in 2 cases,fetal growth restriction was diagnosed in 2 cases,no any abnormalities were found in remaining 7 cases. Seven cases(3 cases of classic 3.0 Mb microduplication, 1 case of proximal microduplication and 3 cases of distal small segment microduplication) were delivered at full-term;and pregnancy was terminated in 4 cases. Seven infants were followed up after birth, 4 infants were normal, 3 showed abnormal phenotypes.Conclusion:The clinical phenotypes after birth of fetuses with 22q11.2 microduplication are diverse. Prenatal genetic counseling is necessary,so that pregnant women and their families can fully understand the possible clinical phenotypes and make informed choices.

Value of chromosomal microarray analysis for genetic evaluation of fetal ultrasound abnormality / 中国辐射卫生

Objective To evaluate the value of chromosomal microarray analysis (CMA) for genetic evaluation of fetal ultrasound abnormality. Methods A total of 180 pregnant women with fetal abnormality detected by prenatal ultrasound diagnosis in the first trimester during the period from January 2020 through May 2022 were enrolled as the study subjects. All prenatal fetal screening samples were subjected to G-band karyotyping and CMA. Results G-band karyotyping detected normal karyotypes in 168 samples (93.85%) and abnormal karyotypes in 11 samples (6.15%), and CMA detected 17 positive samples (9.44%) and 163 negative samples (90.56%). The seventeen positive samples included 11 pathogenic copy number variations (CNVs) and 6 variants of unknown significance (VOUS), and there were 11 CMA-positive results consistent with G-band karyotyping, and 6 additional pathogenic CNVs mainly included microdeletion and microduplication syndromes. The detection rates of pathogenic CNVs were 11.11%, 2.63%, 2.78%, 4.00%, 0, 0, 11.11% and 0 among the fetuses with abnormal structure of the cardiovascular system, the lymphatic system, the nervous system, the digestive system, the cranial and face system, the skeletal system, the urinary system, and other system (χ2 =8.188, P = 0.316). All eleven fetuses with pathogenic CNVs detected by CMA were all induced for abortion. Conclusion CMA improves the detection of genetic abnormality among fetuses with ultrasound abnormality in relative to G-band karyotyping, which is feasible for prenatal cytogenetic diagnosis among fetuses with ultrasound abnormality

Avances genómicos de la última década y su influencia en el enfoque diagnóstico de la discapacidad intelectual / Genomic advances in the last decade and their influence in the diagnosis of intellectual disability

RESUMEN La inteligencia humana es un rasgo poligénico (~1000 genes) con una influencia de cada gen aproximadamente ascendente al 0,1%. Es un atributo indispensable para el desarrollo personal, familiar, social y económico y tiene, además, una relación directamente proporcional al mantenimiento de la salud y a una mayor esperanza de vida. La discapacidad intelectual, consecuentemente, afecta todas estas áreas y constituye un problema de salud pública en varios países de Latinoamérica en los que exhibe una prevalencia mayor al 10%. La etiología de la discapacidad intelectual sea aislada o sindrómica, es genética hasta en un 85% de los casos; se diagnostica mediante las nuevas tecnologías de búsqueda en el genoma, tales como la secuenciación masiva y el análisis cromosómico por micromatrices. El diagnóstico etiológico de la discapacidad intelectual permite la selección de terapias específicas, la determinación del pronóstico y de riesgos de recurrencia familiar e individual.

SUMMARY Human intelligence is a polygenic trait (~1000 genes), with an approximate influence of 0.1% per every individual gen. It is an indispensable attribute for personal, familial, social, and economic development; furthermore, it is directly proportional to health maintenance and a longer life expectancy. Consequently, intellectual disability affects all these areas, and constitutes a public health problem in several Latin American countries where it shows a >10%. In ~85% of the patients, the etiology of intellectual disability, be that isolated or syndromic; it is mostly diagnosed through the new technological search studies of the genome, such as new generation sequencing and/or chromosomal microarray analysis. The clinical and etiological diagnosis of intellectual disability, when duly confirmed, allows the choice of specific treatment modalities, the precise determination of prognosis, and the estimation of individual or familial recurrence risks.

Developmental retardation due to paternal 5q/11q translocation in a Chinese infant: clinical, chromosomal and microarray characterization

Although it is known that the parental carriers of chromosomal translocation are considered to be at high risk for spontaneous abortion and embryonic death, normal gestation and delivery remain possible. This study aims to investigate the genetic factors of a Chinese infant with multiple malformations and severe postnatal development retardation. In this study, the routine cytogenetic analysis, chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) analysis were performed. Conventional karyotype analyses revealed normal karyotypes of all family members. CMA of the DNA of the proband revealed a 8.3Mb duplication of 5q35.1-qter and a 6.9Mb deletion of 11q24.3-qter. FISH analyses verified a paternal tiny translocation between the long arm of chromosomes 5 and 11. Our investigation serves to provide important information on genetic counselling for the patient and future pregnancies in this family. Moreover, the combined use ofCMAand FISH is effective for clarifying pathogenically submicroscopic copy number variants.

Chromosomal Microarray Analysis as a First-Tier Clinical Diagnostic Test in Patients With Developmental Delay/Intellectual Disability, Autism Spectrum Disorders, and Multiple Congenital Anomalies: A Prospective Multicenter Study in Korea

BACKGROUND: To validate the clinical application of chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic test and to determine the impact of CMA results on patient clinical management, we conducted a multicenter prospective study in Korean patients diagnosed as having developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA). METHODS: We performed both CMA and G-banding cytogenetics as the first-tier tests in 617 patients. To determine whether the CMA results directly influenced treatment recommendations, the referring clinicians were asked to complete a 39-item questionnaire for each patient separately after receiving the CMA results. RESULTS: A total of 122 patients (19.8%) had abnormal CMA results, with either pathogenic variants (N=65) or variants of possible significance (VPS, N=57). Thirty-five well-known diseases were detected: 16p11.2 microdeletion syndrome was the most common, followed by Prader-Willi syndrome, 15q11-q13 duplication, Down syndrome, and Duchenne muscular dystrophy. Variants of unknown significance (VUS) were discovered in 51 patients (8.3%). VUS of genes putatively associated with developmental disorders were found in five patients: IMMP2L deletion, PTCH1 duplication, and ATRNL1 deletion. CMA results influenced clinical management, such as imaging studies, specialist referral, and laboratory testing in 71.4% of patients overall, and in 86.0%, 83.3%, 75.0%, and 67.3% of patients with VPS, pathogenic variants, VUS, and benign variants, respectively. CONCLUSIONS: Clinical application of CMA as a first-tier test improves diagnostic yields and the quality of clinical management in patients with DD/ID, ASD, and MCA.

Prenatal diagnosis of a case with Branchi-oto-renal syndrome / 中华医学遗传学杂志

Objective@#To carry out prenatal diagnosis for a women with Branchio-oto-renal syndrome by using chromosomal microarray analysis (CMA).@*Methods@#Peripheral blood chromosomal karyotyping and CMA were used to analyze the gravida with an abnormal phenotype. Pathological copy number variants (CNVs) were validated in other members of the family members and her fetus.@*Results@#The gravida and her daughter both had Branchio-oto-renal syndrome and a 8q13.3 microdeletion encompassing the EYA1 gene. The same microdeletion was also found in the fetus. No phenotypic or genotypic anomaly was found with other members of the family.@*Conclusion@#Mutation of the EYA1 gene probably underlies the Branchio-oto-renal syndrome in this family, which is consistent with an autosomal dominant inheritance.

Molecular cytogenetic diagnosis of a case with ring chromosome 18 syndrome / 中华医学遗传学杂志

Objective@#To explore the genetic basis for a child with developmental delay and congenital syndactyly.@*Methods@#G-banding chromosomal karyotyping and chromosomal microarray analysis (CMA) were performed on peripheral blood sample from the child.@*Results@#The child was ascertained as 46, XY, r(18)[52]/45, XY, ? 18[3]. A 18q21.32-q23 deletion was identified by CMA with a size of 19.85 Mb, which has encompassed 99 genes including CTDP1, TXNL4A, TSHZ1, PIGN, RTTN, TNFRSF11A, KDSR and CYB5A.@*Conclusion@#Clinical phenotype of the patient with ring chromosome 18 is associated with the size of the euchromatin loss and involved genes. As a useful complement to conventional karyotyping, CMA has provided an powerful tool for delineating complex chromosomal aberrations.

Application of chromosomal microarray analysis in prenatal diagnosis of fetuses with increased nuchal translucency / 中华医学遗传学杂志

Objective@#To determine the frequency of chromosomal abnormalities and outcome of pregnancy for fetuses with increased nuchal translucency (NT).@*Methods@#Between July 2014 and February 2018, 247 fetuses with increased NT (>95th centile)were analyzed by chromosome microarray analysis (CMA). The fetuses were divided into ones with isolated increased NT(168 cases), increased NT with cystic hygroma(20 cases), increased NT with edema(12 cases) or increased NT with other abnormalities(47 cases). All couples were followed up by telephone calls.@*Results@#The rate of chromosomal abnormalities was 31.6% (78/247), which included 66 cases with chromosomal aneuploidies and 12 with copy number variants(CNVs). CNVs accounted for 31.4% (11/35) of total abnormalities among fetuses with isolated increased NT, whilst only 2.3% (1/43)of the total abnormalities among fetuses with non-isolated increased NT. Three fetuses with a normal CMA result had mental and physical retardation. Two of them were diagnosed with single gene disorders by whole exome sequencing.@*Conclusion@#CMA can detect more chromosomal microdeletion/microduplications among fetuses with isolated increased NT. Furthermore, fetuses with increased NT and anegative CMA result during pregnancy cannot exclude all adverse outcomes.

Clinical analysis of 15 cases with abnormal chromosomal microarray analysis results at endocrinology clinic / 中华实用儿科临床杂志

Objective To explore the application value of chromosomal microarray analysis(CMA)technolo-gy in children with abnormal development at the endocrine clinic,and to summarize the data of diagnosis and treatment. Methods A retrospective analysis of 15 children with abnormal development was performed at the endocrinology clinic of Guangzhou Women and Childrenˊs Medical Center from January 2015 to December 2017. The whole genome CMA was applied according to the standard operation procedure of CytoScan 750 arrays of Affymetrix,USA. The results were analyzed by chromosome analysis suite( CHAS)software and related bioinformatics methods. Results The report on CMA showed that the genomes of 15 children had the pathogenic copy number variation(CNVs)or variants of uncer-tain significance. The chromosomal abnormalities were consistent with the clinical manifestations of all children. There were deletions in 14 cases and duplications in 3 cases. Among the 15 cases,loss of heterozygosity was found in 2 cases, uniparental disomy in 1 case,trisomy in 2 cases,Turner syndrome in 2 cases,Smith-Magenis syndrome in 1 case,and wolf Hirschhorn syndrome in 1 case. Only 2 of 15 children were diagnosed as chromosomal abnormalities by routine kar-yotype analysis. Conclusions The whole genome high resolution CMA can significantly improve the rate of diagnosis in children with abnormal development at endocrinology clinic,and is worthy of recommendation.

Genetic Syndromes and Associated Cariovascular Anomalies in Adults: A Singapore Perspective

@#Children with genetic syndromes are increasingly surviving to adulthood in Singapore. This is due to early detection and significantly improved multi-dimensional care. Congenital heart disease is one of the characteristic abnormalities in patients. However, the cardiac anomalies of some of these patients may only manifest later in early adulthood. A significant number of such patients are not on regular medical follow-ups to monitor for future complications. This article describes based on the common syndromic conditions that are present in Singapore. Advanced genetic tests like chromosomal microarray analysis can help diagnose these syndromes that are not obvious clinically, thus instituting appropriate management and treatment for such patients. Creating awareness of such syndromes and its cardiac complications will translate to them being referred to the cardiologists to prevent further morbidity and mortality. Timely counselling regarding fertility, prenatal testing and complications due to pregnancy are also discussed in this article.

Prenatal ultrasonic manifestations and prognostic analysis of 17q12 microdeletion syndrome / 中华超声影像学杂志

Objective To summarize and analyze the prenatal ultrasonic manifestations of 17q12 microdeletion syndrome ,so as to provide help for prenatal diagnosis . Methods It carried out a retrospective analysis of 21 cases of 17q12 microdeletion syndrome prenatally confirmed by chromosomal microarray analysis(CMA) in the third affiliated hospital of Zhengzhou University from 2015 .01 to 2018 .05 . Prenatal ultrasound findings were collected . A close follow-up was given for the cases . Results Of the 21 fetus ,20 cases were presented with bilateral hyperechogenic kidneys ,and 1 case showed duodenal obstruction . There were 4 cases accompanied with polyhydramnios ,8 cases with mild polyhydramnio ,and 9 cases with normal amniotic fluid index . Parents of 6 fetus underwent chromosomal examination ,of which 2 cases were inherited from the mother and 4 cases had new chromosomal mutations;Seven cases had a family history of diabetes and 3 cases had a family history of kidney disease;Twelve cases performed induced labor ,2 cases lost follow-up and 1 case was unborn . Six cases were born ,of the 6 cases ,1 case associated with mild dysmorphic facial features , and 1 case associated with bilateral renal cysts . Conclusions 17q12 microdeletion syndrome has specific prenatal ultrasound characteristics ,while echogenic kidneys are of great value in the diagnosis of 17q12 microdeletion syndrome prenatally .

One case report of Jacobsen syndrome combine with Paris-Trousseau syndrome / 临床儿科杂志

Objective To investigate the clinical features of a patient diagnosed with Jacobsen syndrome (JBS) and Paris-Trousseau syndrome (PTS) using chromosomal microarray analysis. Method A retrospective analysis including the patients' clinical manifestations, laboratory examination and genetic analysis was carried out and related literature were reviewed. Results A 14 month-old girl with global development retardation was reported. The patient can sit but cannot walk independently. The patient also presented hypsicephaly, ocular hypertelorism, palpebral ptosis, flat nasal bridge, sparse eyebrows, and speech delay. Gesell development scale showed that the patient was global development retarded with a development level of 40 weeks. No o bvious abnormality was found in EEG but the MRI showed cerebral white matter abnormality. This patient was also diagnosed with neonatal thrombocytopenia in other hospital. Genomic CNVs were detected in this girl, and a 15.7Mb loss was found in the 11q23.3q25 region that covers JBS and PTS region. Conclusions Patient diagnosed with JBS and PTS often present with craniofacial abnormalities, cerebral white matter abnormality and neonatal thrombocytopenia. Chromosomal microarray analysis can help diagnosis.

Application value of chromosomal microarray analysis in prenatal diagnosis of lateral ventriculomegaly fetuses / 解放军医学杂志

Objective To analyze the genetic etiology of lateral ventriculomegaly fetal on the genome-wide level with chromosomal microarray analysis (CMA),and investigate the relationship between copy number variations (CNVs) and lateral ventriculomegaly and the application value of CMA in prenatal diagnosis of fetuses with lateral ventriculomegaly.Methods Seventy fetuses with lateral ventriculomegaly but normal or uncertain karyotype were selected and invasive prenatal diagnosis was performed in Xi Jing Hospital of the Fourth Military Medical University from Jan.2015 to Nov.2016.Microarray testing was performed using Affymetrix CytoScanTM 750k arrays and the results were analyzed according to biological information science database.The fetal development was regularly inspected,and follow up was conducted to find out the pregnancy outcome and fetal postnatal conditions.Results In 70 cases of lateral ventriculomegaly fetuses,there were 9 fetuses with pathogenic copy number variations (CNVs),3 fetuses with likely pathogenic CNVs and 1 fetus with likely pathogenic 1 oss of heterozygosity (LOH).During the 70 fetuses with lateral ventriculomegaly,2 pathogenic CNVs were detected in 6 fetuses with severe and non isolated lateral ventriculomegaly (33.3％).Pathogenic CNVs was not detected but 1 likely pathogenic CNV was detected in 3 fetuses with severe and isolated lateral ventriculomegaly (33.3％).Six pathogenic CNVs were detected in 31 mild and non isolated lateral ventriculomegaly (19.4％),and 2 likely pathogenic CNVs were also detected in these group (6.5％).One pathogenic CNV and 1 likely pathogenic CNV were detected in 30 fetuses with mild and isolated fetal lateral ventriculomegaly.Conclusions CMA can identify chromosome abnormality microdeletion/microduplication which was unrecognizable by conventional karyotyping analysis.The application of CMA may increase the detection rate of pathogenic CNVs in fetuses with lateral ventriculomegaly,and benefit evaluation of fetal prognosis in prenatal genetic counselling.

One case of chromosome 4q21/22 deletion syndrome / 临床儿科杂志

Objective To enhance the understanding of clinical characteristics and genetic testing of chromosome 4q21/q22 deletion syndrome. Methods Chromosomal microarray analysis was used to detect genetic change in a child with special facial appearance and development delay. Results A 15.26-Mb deletion containing 76 geinges in chromosome 4q21.21q22.2 was identiifed. Thus, this girl was diagnosed as chromosome 4q21/q22 deletion syndrome. Conclusions Chromosome 4q21/q22 deletion syndrome has varied clinical manifestations including typical characteristics (such as absolute or relative macrocephaly, megalencephaly with a characteristic head shape and facial appearance, profound hypotonia, small hands and feet, short limbs, feeding difficulties), mental retardation/severe developmental delay, and other system abnormalities ( such as congenital heart disease, seizure, kidney cysts, etc). The diagnosis of chromosome 4q21/q22 deletion syndrome relies on chromosomal microarray analysis.