¿Qué puede esconder el retraso global del desarrollo? A propósito de un caso de causa genética / What can Global Developmental Delay Conceal? Apropos of a Case with a Genetic Cause

Se presenta un niño de 6 años con antecedente de retraso del lenguaje que llevó a sus padres a realizar múltiples consultas. En un primer momento, su cuadro fue interpretado como parte de un retraso global del desarrollo. Posteriormente, el paciente presentó convulsiones y episodios de descompensación metabólica, comenzando desde entonces su seguimiento por los Servicios de neurología, genética y metabolismo. Finalmente, tras varios estudios complementarios, por medio de un exoma trío se arribó al diagnóstico de síndrome de microduplicación del cromosoma 7q11.23, lo que justifica tanto el retraso global de desarrollo del paciente como su clínica neurológica. (AU)

A six-year-old boy presents with a history of language delay that led his parents to make multiple consultations. At first, we interpreted his condition as part of a global developmental delay. Subsequently, the patient presented seizures and episodes of metabolic decompensation, and since then, he had to be followed up by neurology, genetics, and metabolism services. Finally, after several complementary studies, following a trio exome analysis, we diagnosed chromosome 7q11.23 microduplication syndrome, which explains his global developmental delay and neurological symptoms. (AU)

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.

5p13. 2 Chromosomal duplication syndrome: case report and literature review / Síndrome de duplicação cromossômica 5p13. 2: relato de caso e revisão da literatura

Chromosome 5p13 duplication syndrome represents a contiguous gene syndrome involving duplication of several genes on chromosome 5p13. Some clinical phenotypes are related to it, such as: obsessive-compulsive behavior, small palpebral fissures, intellectual disability, global development delay and ocular hypertelorism. The exact mechanism behind these changes has not well known and further studies are needed for this purpose. Since it is a rare and uncommon clinical situation, the case report contributes to the knowledge of the disease and early diagnosis. This condition mainly affects the cognitive neuromuscular system. We describe an 8-year-old Brazilian patient with the duplication of chromosome 5p13.2, karyotype, whose neurodevelopmental evaluation presented cognitive impairment, severe language delay and atypical physical examination, with ocular hypertelorism, right auricular tags, congenital heart defect and long fingers. The patient was diagnosed by comparative genomic hybridization (CGH)-array revealing a 204Kb of DNA duplication. The exact mechanism behind these structural disorders is still unclear and further studies are needed for this purpose. Nevertheless, the diagnostic suspicion of this genetic alteration that, in general, presents late diagnosis, should be considered to enable better clinical support to the patients and family genetic counseling.

A síndrome da duplicação do cromossomo 5p13 representa uma síndrome genética contígua envolvendo a duplicação de vários genes contidos nesta região. Alguns fenótipos clínicos estão relacionados com ela, tais como: comportamento obsessivo compulsivo, fissuras palpebrais pequenas, déficit intelectual, atraso no desenvolvimento global e hipertelorismo ocular. Por ser uma situação clínica rara, o relato do caso contribui para a disseminação do conhecimento acerca da condição, assim como para seu diagnóstico precoce. Descrevemos uma paciente brasileira de oito anos com a duplicação do cromossomo 5p13.2, que na avaliação do neurodesenvolvimento apresentou comprometimento cognitivo, grave atraso da linguagem e dismorfismos como hipertelorismo ocular, apêndice auricular direito, sopro cardíaco, relacionado a defeito do septo ventricular, e dedos alongados. A paciente foi diagnosticada por meio da pesquisa molecular (CGH)-array com ganho de 204Kb de DNA. O mecanismo exato por trás dessas alterações estruturais ainda não está claro e são necessários mais estudos para este fim. Não obstante, a suspeita diagnóstica dessa alteração genética que, em geral, apresenta diagnóstico tardio, deve ser aventada para viabilizar melhor suporte clínico aos pacientes e aconselhamento genético familiar.

Genetic analysis of a pedigree affected with congenital split-hand/foot malformation / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with split hand/foot malformation (SHFM).@*METHODS@#Genomic DNA of the proband and other affected members was extracted from peripheral blood samples. Chromosomal microarray analysis was employed to detect genome-wide copy number variations (CNVs).@*RESULTS@#A 400 kb microduplication was identified in the 10q24.31-q24.32 region among all affected individuals. The microduplication has involved four genes, namely LBX1, BTRC, POLL and DPCD, in addition with part of FBXW4 gene.@*CONCLUSION@#The 10q24.31-q24.32 microduplication has segregated with the disease phenotype in this pedigree and probably underlay the SHFM malformation in the patients.

Genetic analysis of an infant with duplication of 22q12.1-q13.3 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for an infant with multiple malformations including congenital heart disease and cleft palate.@*METHODS@#The child and his parents were subjected to conventional chromosomal karyotyping and low-coverage massively parallel copy number variation sequencing (CNV-seq) analysis.@*RESULTS@#The infant was found to have a 46,X,add(Y)(q11.23) karyotype, and his CNV-seq result was seq [hg19] 22q12.1q13.3 (29 520 001-51 180 000)× 3. His parents were found to be normal by both methods.@*CONCLUSION@#The additional chromosomal material found on Yq, verified as duplication of 22q12.1-q13.3, may account for the abnormal phenotype in this infant. CNV-seq has provided a useful complement for the diagnosis and more accurate information for genetic counseling.

Identification of a 17q25.3 duplication in a Chinese patient with global developmental delay and multiple congenital anomalies / 中华医学遗传学杂志

OBJECTIVE@#To delineate the clinical features,inheritance pattern, and genotype-phenotype correlation of a Chinese patient with a 17q25.3 duplication.@*METHODS@#Whole exome sequencing(WES), chromosomal microarray analysis (CMA), chromosomal karyotyping and fluorescence in situ hybridization (FISH) were employed for the analysis of the proband and his family members.@*RESULTS@#A 5.7 Mb duplication at 17q25.3→qter was identified by WES and CMA in the 4-year-old boy with multiple congenital anomalies, which was classified as a clinically pathogenic variant. This duplication was confirmed by FISH, and was inherited from his unaffected mother who carried a balanced translocation. Further study revealed that his grandmother also carried the balanced translocation but had gestated three healthy children and had no abortion history. His uncle also carried the balanced translocation, while his aunt was normal.@*CONCLUSION@#Above results have enriched the clinical phenotypes of 17q25.3 duplication. Genetic counseling was provided for the family. P4HB, ACTG1, BAIAP2 and TBCD genes may underlie the clinical features for the 17q25.3 duplication.

Clinical and genetic study of a child with 15q11.2 microduplication / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a child with developmental delay and intellectual disability.@*METHODS@#Peripheral blood samples of the child and his parents were collected for routine G-band karyotyping analysis and single nucleotide polymorphism array (SNP array) assay. Amniotic fluid sample was collected during the next pregnancy for prenatal diagnosis.@*RESULTS@#No karyotypic abnormality was found in the child and his parents. SNP array showed that the child has carried a 855.3 kb microduplication in 15q11.2. His mother carried the same duplication but had no phenotypic anomaly. No microdeletion/microduplication was found in his father. Upon prenatal diagnosis, no abnormalities was found with the chromosomal karyotype and SNP array result of the fetus.@*CONCLUSION@#15q11.2 microduplication may result in developmental delay and intellectual disability, for which CYFIP1 may be a candidate gene. However, the duplication may increase the risk but with a low penetrance. This should attract attention during clinical consultation.

Prenatal diagnosis of three fetuses with small supernumerary marker chromosomes / 中华医学遗传学杂志

OBJECTIVE@#To explore the origin and mechanism of small supernumerary marker chromosomes (sSMC) in three fetuses.@*METHODS@#The three fetuses were predicted to have carried chromosomal abnormalities by non-invasive prenatal testing (NIPT). G-banding chromosomal karyotyping analysis were carried out on amniotic fluid samples of the fetuses and peripheral blood samples from their parents. Single nucleotide polymorphism array (SNP-array) was used to determine the origin, size and genetic effect of sSMCs.@*RESULTS@#In fetus 1, SNP array has detected two microduplications respectively at 4p16.3p15.2 (24.7 Mb) and 18p11.32q11.2 (20.5 Mb) which, as verified by fluorescence in situ hybridization (FISH), have derived from a balanced 46,XY,t(4;18)(p15.2q11.2) translocation carried by its father. Fetus 2 has carried a de novo microduplication of 15q11.2-q13.3 (9.7 Mb). The sequence of SMC in fetus 3 has derived from 21q11.2-q21.1 (8.3 Mb), which was inherited from its mother.@*CONCLUSION@#Both NIPT and SNP-array are highly accurate for the detection of sSMC. SNP-array can delineate the origin and size of abnormal chromosomes, which in turn can help with clarification of sSMC-related genotype-phenotype correlation and facilitate prenatal diagnosis and genetic counseling for the family.

Prenatal diagnosis and pregnancy outcomes of 22q11.2 duplication syndrome: analysis of 8 cases / 浙江大学学报·医学版

OBJECTIVE@#To investigate the relationship between 22q11.2 duplication and clinical phenotype.@*METHODS@#Eight fetuses with 22q11.2 duplication syndrome diagnosed by chromosome microarray analysis (CMA) through amniocentesis from February 2015 to March 2017 were enrolled in the study. The prenatal diagnostic indications, fetal ultrasound, chromosome karyotype, peripheral blood CMA results of parents, pregnancy outcomes and follow-up of postnatal growth and development were retrospectively analyzed.@*RESULTS@#Prenatal serological screening indicated 6 cases with high risk of trisomy 21, 1 case with nuchal fold (NF) thickening and 1 case of maternal chromosomal balanced translocation. Fetal ultrasonography showed 1 case of NF thickening, 1 case of fetal cerebral ventriculomegaly and 6 cases with normal ultrasound. CMA demonstrated that the size of duplication was between 651 kb and 3.26 Mb, and 22q11.2 duplication. Parents' CMA results revealed that 6 cases inherited from one of the parents with normal phenotype, and the parents of 2 cases refused the CMA test. Two couples chose induced labor; 6 cases of continued pregnancy had normal phenotypes at birth. All 6 cases were followed up with longest of 3.5 years. The growth and psychological development were normal in 5 cases, and one case was growth retardation.@*CONCLUSIONS@#There were no specific clinical phenotypes in 22q11.2 duplication syndrome, and most of them were inherited from one parent who has normal phenotype.

Genetic analysis of a child with mental retardation and hypospadia / 中华医学遗传学杂志

OBJECTIVE@#To carry out genetic testing for a boy presenting with mental retardation and hypoplasia.@*METHODS@#Conventional karyotyping, fluorescence in situ hybridization (FISH) and single nucleotide polymorphism based array (SNP-array) were used to analyze the boy and his parents.@*RESULTS@#SNP-array has detected a 25.7 Mb microduplication at 2q33.3q36.3 in the boy. Chromosomal karyotyping and FISH analysis indicated that his mother had a karyotype of 46,XX,ish ins(11;2) (p15;q33q36), and that the boy has carried an abnormal chromosome 11 derived from the maternal translocation. The karyotype of the boy was ascertained as 46,XY,ish der(11)ins(11;2) (p15;q33q36)mat.@*CONCLUSION@#SNP-array combined with G-banding and FISH can delineate the cryptic translocation and is valuable for the assessment of recurrence risk for subsequent pregnancies.

Genetic diagnosis of a child with Smith-Magenis syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the molecular mechanism of a girl with developmental delay and intellectual disability.@*METHODS@#Chromosomal karotypes of the child and her parents were analyzed with routine G-banding method. Their genomic DNA was also analyzed with array comparative genomic hybridization (aCGH) for chromosomal duplications/deletions.@*RESULTS@#No karyotypic abnormality was detected in the child and her parents, while aCGH has identified a de novo 3.37 Mb deletion at 17p11.2 in the child.@*CONCLUSION@#The child was diagnosed with Smith-Magenis syndrome, for which RAI1 may be the causative gene.

Phenotypic and genetic analysis of a pedigree with 4p16 microduplication and 8p23 microdeletion / 中华医学遗传学杂志

OBJECTIVE@#To explore the nature and origin of chromosomal copy number variants (CNVs) in a pedigree affected with mental retardation.@*METHODS@#Genomic CNVs of the proband were analyzed by next generation sequencing (NGS). Chromosomal karyotypes of the proband and his relatives were analyzed with high-resolution karyotyping and fluorescence in situ hybridization (FISH).@*RESULTS@#Clinical phenotypes of the proband and other patients from the pedigree included mental retardation and mild dysmorphism. The results of NGS revealed that the proband carried a 16.24 Mb microduplication at 4p16.3-15.32 and a 2.2 Mb microdeletion at 8p23.3-23.2. Other patients of the pedigree harbored the same variants, while those without the phenotypes did not harbor the variants. The results of high-resolution karyotyping and FISH revealed that the mother of the proband carried a reciprocal translocation between 4p and 8p, and her karyotype was 46,XX,t(4;8)(p16;p23). No karyotypic abnormality was detected in his father.@*CONCLUSION@#The abnormal phenotypes of this pedigree may be attributed to 4p microduplication in conjunct with 8p microdeletion derived from a maternal balanced translocation between 4p and 8p.

Identification of pathogenic mutation in a Chinese pedigree affected with split hand/split foot malformation / 中华医学遗传学杂志

OBJECTIVE@#To detect potential mutation in a Chinese pedigree affected with split hand/split foot malformation (SHFM).@*METHODS@#The patients were screened for genome-wide copy number variations with single nucleotide polymorphism (SNP) microarray. Copy number variations were verified by real-time fluorescence quantitative PCR.@*RESULTS@#There were 3 SHFM patients from three generations, which conformed to an autosomal dominant inheritance. SNP microarray assay revealed that all patients have carried a 0.34 Mb duplication in 10q24.31-q24.32 (102 993 649-103 333 271) encompassing the BTRC and DPCD genes. The result was verified by real-time fluorescence quantitative PCR, confirming that the duplication has co-segregated with the SHFM phenotype in the pedigree.@*CONCLUSION@#The 10q24.31-q24.32 duplication probably underlies the pathogenesis of SHFM in this pedigree. Tiny copy number variations can result in diseases featuring autosomal dominant inheritance.

Clinical and molecular cytogenetic analysis of a family with mental retardation caused by an unbalanced translocation involving chromosomes 3 and 22 / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the genetic cause of a Chinese boy with unexplained mental retardation, and analyze the pattern of inheritance for his family.</p><p><b>METHODS</b>Routine karyotyping, chromosomal microarray analysis (CMA), and fluorescence in situ hybridization (FISH) were used to detect chromosome abnormalities in the patient and his families.</p><p><b>RESULTS</b>Chromosome analysis suggested that the proband and 7 affected individuals had an identical karyotype 46,XN,der(22)t(3;22)(q28;q13)pat, while his father and 5 other relatives carried a same karyotype of 46,XN,t(3;22)(q28;q13). His mother and other family members were normal. CMA analysis confirmed that the patient had a 9.0 Mb duplication at 3q28q29, in addition with a 1.7 Mb deletion at 22q13.3. Above results were confirmed by FISH.</p><p><b>CONCLUSION</b>The abnormal phenotypes of the proband and his family members from five generations have conformed to those of 3q duplication and 22q13.3 deletion caused by unbalanced translocation involving chromosomes 3q and 22q. The presence of multiple patients in this family may be attributed to abnormal gametes produced by parental balanced translocations involving 3q and 22q.</p>

Prenatal diagnosis of a case with 46,XX,del(4),dup(21) / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the genetic cause and prognosis of a fetus with a rare karyotype.</p><p><b>METHODS</b>Fluorescence in situ hybridization (FISH) was used for verifying a structural chromosomal abnormality detected by conventional karyotyping analysis. Whole genome DNA microarray was used to analyze copy number variations carried by the fetus.</p><p><b>RESULTS</b>The fetus was found to have a 46,XX,dup(21)(?q21q22) karyotype, which was verified by FISH analysis as repetition of chromosome 21 region, namely nuc ish 21q22×3. Whole genome DNA microarray confirmed that there was a 17.87 Mb duplication in the 21q21.3q22.3 region, which involved GATA1, JAK2 and ALL genes and spanned the Down syndrome region. The genes are implicated in craniofacial abnormalities, cardiac abnormalities, mental retardation, growth retardation, limb abnormalities. In addition, there was also an 8.43 Mb deletion in the 4p16.1p16.3 region, which involved FGFR3, LETM1, WHSC1 and WHSC2 and other 64 OMIM genes and spanned the Wolf-Hirschhorn syndrome region. The genes are implicated in growth retardation, craniofacial abnormalities, cardiac abnormalities, mental retardation, and hypotonia. After consultation, the family chose to terminate the pregnancy at 25th week of gestation.</p><p><b>CONCLUSION</b>FISH can help to verify structural chromosome abnormalities suspected by conventional karyotyping analysis. Combined with whole genome microarray, these can determine copy number variation and its region containing the disease genes, and facilitate clinical analysis of the fetus.</p>

Analysis of the cause of pregnancy failure with combined MLPA assay for subtelomeric regions and ultrasonography / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the value of multiplex ligation-dependent probe amplification (MLPA) for the detection of chromosome abnormalities in miscarriage tissues, and to correlate the result with ultrasound findings.</p><p><b>METHODS</b>A total of 421 cases of spontaneous abortions and fetal deaths were detected with the MLPA method.</p><p><b>RESULTS</b>Among the 421 samples, 232 (55.11%) had an abnormal MLPA result. For the 286 cases derived from < 13 weeks pregnancy, 206 (72.03%) were abnormal. For the 49 cases from 14-19 weeks pregnancy, 14 (28.57%) were abnormal. For the 86 cases derived after 20 weeks pregnancy, 12 (13.95%) were abnormal. Among the 117 cases with abnormal ultrasound findings, 33 cases (28.21%) had an abnormal MLPA result, 28 out of the 33 cases were numerical chromosome abnormality, 4 cases were chromosome microdeletion and/or micro duplication, 1 case had both numerical abnormality and microduplication. For those with abnormal ultrasound findings for the neck region, fetal edematous syndrome, multiple malformations and digestive system, the detection rates for MLPA were 71.4%, 58.8%, 37.8%, and 9.1%, respectively. For those with abnormal finding of cardiac system, nervous system, face, skeletal system and urinary system, none was found with positive results of MLPA.</p><p><b>CONCLUSION</b>Numerical chromosomal abnormalities account for the majority of cases with spontaneous abortion. With the increase of gestational age, the occurrence of chromosomal abnormalities gradually declines. Combined ultrasound and MLPA assay can improve the detection rate and accuracy for chromosomal abormalities.</p>

Analysis of isodicentric Ph chromosomes in chronic myeloid leukemia blast crisis / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the genetic and clinical characteristics of isodicentric Ph chromosomes [idic(Ph)] in lymphoid blast crisis of chronic myeloid leukemia (CML-BLC).</p><p><b>METHODS</b>Bone marrow aspirates of 2 patients with CML-BLC were analyzed by R banding after 24 hours of culturing. Genomic copy number variations (CNV) were analyzed by single nucleotide polymorphism array (SNP array) in case 1. The results were confirmed with fluorescence in situ hybridization (FISH). Variations of acute lymphoblastic leukemia-related genes including CDKN2A/AB and PAX5 were detected by multiplex ligation-dependent probe amplication (MLPA).</p><p><b>RESULTS</b>Deletions and duplications on derivative chromosome 9 detected by FISH were confirmed by SNP array analysis. The distances between the BCR/ABL fusion signals on the idic(Ph) chromosomes in the two patients have differed greatly. The idic(Ph) in the second patient was supposed to be formed by two Ph chromosomes joined at their q terminals, where as the idic(Ph) in the first patient have been shown to be fused at the satellite regions of their p arms.</p><p><b>CONCLUSION</b>The idic(Ph) chromosomes presented in CML-BLC may predict resistance to Imatinib and response to Dasatinib.</p>

Hibridación genómica comparativa: su interpretación y uso como herramienta diagnóstica en retardo mental inespecífico y síndromes de microdeleción/microduplicación / Comparative genomic hybridization: its interpretation and use as a diagnostic tool in nonspecific mental retardation and microdeletion/microduplication syndromes

En Colombia el cariotipo por bandeo es todavía la prueba inicial más usada en el estudio de pacientes con retardo mental o con anomalías congénita múltiples. Sin embargo, las técnicas moleculares, particularmente la hibridación genómica comparativa con microarrays, han permitido identificar un número creciente de síndromes de microduplicación o microdeleción en estos pacientes, de modo que mundialmente esta es hoy en día la tecnología de elección para evaluar alteraciones del número de copias. Se realiza esta revisión de la literatura con el objetivo de brindar al personal médico información actualizada acerca de la interpretación y el papel de la hibridación genómica comparativa con microarrays como herramienta diagnóstica en retardo mental inespecífico, síndromes de microdeleción/ microduplicación y análisis cromosómico prenatal. MÉD.UIS. 2016;29(2):137-44.

In Colombia the banding karyotype is still the initial test used in the study of patients with mental retardation or with multiple congenital anomalies. However, molecular techniques, particularly comparative genomic hybridization with microarray have identified a growing number of microdeletion or microduplication syndromes in these patients, so that globally this is the technology of choice nowaday for evaluating copy number alterations. This literature review is aimed at providing to medical personnel the latest information regarding the interpretation and role of comparative genomic hybridization as a diagnostic tool in nonspecific mental retardation, microdeletion/ microduplication syndromes and prenatal chromosomal analysis. MÉD.UIS. 2016;29(2):137-44.

Síndrome de duplicación 7q11. 23: Primer caso descrito en América Latina / Chromosome 7q11. 23 duplication syndrome: First reported case in Latin America

El síndrome de duplicación 7q11.23 es una patología causada por la duplicación de una región del cromosoma 7 que comprende 26 genes. El primer caso descrito en la literatura fue reportado por Somerville et al., en el año 2005, quienes describieron un paciente con dolicocefalia, frente alta y estrecha, pestanas largas, nariz alta y ancha, filtrum corto, paladar ojival, maloclusión dental, retrognatia y retardo grave en el lenguaje. Presentamos una paciente colombiana con hallazgo de duplicación 7q11.23 mediante técnicas de hibridación genómica comparativa y hallazgos clínicos clásicos. Este es el primer caso comunicado en Colombia y en América Latina.

7q11.23 duplication syndrome is a disease caused by duplication of a region of chromosome 7 comprising 26 genes. The first case described in the literature was reported by Somerville et al. in 2005, who described a patient with dolichocephaly, high and narrow forehead, long eyelashes, high and wide nose, short philtrum, high arched palate, dental malocclusion, retrognathia, and severe language delay. We report the case of a Colombian patient with 7q11.23 duplication by comparative genomic hybridization techniques, and classical clinical findings, this being the first reported case in Colombia and Latin America.

Clinical phenotypes and copy number variations in children with microdeletion and microduplication syndromes: an analysis of 50 cases / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the association between genotype and phenotype of microdeletion and microduplication syndromes (MMSs) and the pathogenesis of pathogenic copy number variations (CNVs).</p><p><b>METHODS</b>A total of 50 children with MMSs diagnosed by chromosomal microarray analysis (CMA) from June 2013 to September 2015 were enrolled, and the clinical manifestations and features of pathogenic CNVs were analyzed.</p><p><b>RESULTS</b>The main clinical manifestations of children with MMSs included mental retardation, developmental delay, short stature, and unusual facies, with the presence of abnormalities in multiple systems. There were 54 pathogenic CNVs in total, consisting of 36 microdeletion segments and 18 microduplication segments, with sizes ranging from 28 kb to 48.5 Mb (mean 13.86 Mb). Pathogenic CNVs often occurred in chromosomes X, 15, and 1.</p><p><b>CONCLUSIONS</b>The clinical manifestations of MMSs are not specific, and a genotype-first approach can be used for diagnosis. Mode of inheritance, type of recombination (deletion or duplication), size of segment, and functional genes included helps with the interpretation of CNVs of de novo mutations, and in-depth research on rare pathogenesis may become breakthrough points for the identification of new MMSs.</p>