三例Kleefstra综合征患儿临床和遗传学分析

目的对3例不明原因的发育迟缓(developmental delay, DD)/智力障碍(intellectual disability, ID)患儿进行临床症状和染色体微阵列分析(chromosome microarray analysis, CMA), 明确其可能的病因。方法采集3例DD/ID患儿的外周静脉血样, 进行CMA检测。结果例1的9号染色体q34.3区段约有190 kb的DNA片段缺失, 包含Kleefstra综合征(OMIM 610253)的关键基因EHMT1(OMIM 607001)的大部分区域;例2和例3为同胞姐妹, CMA检测显示均存在相同的4处染色体片段异常, 其中9号染色体q34.3区域缺失长度分别是154 kb和149 kb, 均包含EHMT1和CACNA1B(OMIM 601012)基因, 其余变异无临床意义。结论 3例患儿的染色体9q34.3微缺失可能是其DD/ID的致病原因, EHMT1是关键基因。     

Clinical and genetic analysis of three children patients with Kleefstra syndromeCSCD

Objective To explore the genetic basis of three children with unexplained developmental delay/intellectual disability (DD/ID). Methods Peripheral blood samples were collected from the patients and subjected to chromosomal microarray analysis (CMA). Results Patient 1 was found to harbor a 190 kb deletion at 9q34.3, which encompassed most of EHMT1 (OMIM 607001), the key gene for Kleefstra syndrome (OMIM 610253). Patients 2 and 3 were siblings. CMA showed that they have shared four chromosomal copy number variations (CNVs) including a deletion at 9q34.3 which spanned 154 kb and 149 kb, respectively, and encompassed the EHMT1 and CACNA1B (OMIM 601012) genes. The remaining 3 CNVs were predicted to be with no clinical significance. Conclusion Microdeletions at 9q33.4 probably underlay the pathogenesis of DD/ID in the three children, for which EHMT1 may be the key gene. © 2022 West China University of Medical Sciences. All rights reserved.     

Clinical and molecular description of a 17q21.33 microduplication in a girl with severe kyphoscoliosis and developmental delay

High proportion of disease-associated copy number variant maps to chromosome 17. Genomic studies have provided an insight into its complex genomic structure such as relative abundance of segmental duplication and intercepted repetitive elements. 17q21.31, 17q11.2 and 17q12 loci are well known on this chromosome and are associated with microdeletion and microduplication syndrome. No syndrome associated with 17q21.33 locus have been described.We report clinical, cytogenetic and molecular investigations of a 13 years-old girl admitted for evaluation of microcephaly, scoliosis, skeletal defects and learning difficulties. We carried out detailed analysis of the clinical phenotype of this patient and investigated the genetic basis using Agilent 180K Array Comparative Genomic Hybridization.We identified a ∼0.9 Mb de novo microduplication on chromosome 17q21.33. Four genes, COL1A1, SGCA, PPP1R9B and CHAD located within the duplicated region are possible candidates for clinical features present in our patients. Gene expression studies by real-time RT-PCR assay only showed an overexpression of SGCA (P < 0.01), a component of the dystrophin glycoprotein complex. Defect of SGCA was previously shown to lead to severe childhood autosomal recessive muscular dystrophy (LGMD2D) which result in progressive muscle weakness and can also be associated with hyperlordosis or scoliosis. Further cases with similar duplications are expected to be diagnosed. This will contribute to the delineation of this potential new microduplication syndrome and to improve genetic counseling.     

拷贝数变异分析对于不明原因智力障碍/发育迟缓患儿的诊断价值

目的:评估拷贝数变异(copy number variations,CNVs)分析在智力障碍/发育迟缓(intellectual disability/developmental delay, ID/DD)患者遗传学病因诊断中的价值。方法:对2015年1月至2019年12月本院确诊为ID/DD的530例患儿进行核型分析...     

一例Sifrim-Hitz-Weiss综合征患儿的临床与CHD4基因变异分析

目的探讨一例Sifrim-Hitz-Weiss综合征(Sifrim-Hitz-Weiss syndrome,SIHIWES)患儿的基因型与表型的对应关系。方法收集先证者及其父母的外周血样,提取基因组DNA,采用全外显子测序对先证者进行检测,并应用Sanger测序对先证者及父母进行验证。结果先证者为一例2岁女性患儿,表现为全面发育迟缓、智力障碍、特殊面容等。其产前表现为NT增厚,颅面部异常和胎动减少等。全外显子测序发现患儿CHD4基因发生了致病性变异NM_001273:c.2989C>G(p.Leu997Val)(GRCh37/hg19)。与以往报道的SIHIWES的临床表型相比,该患儿产前临床特征未有描述,而产后某些新的表型包括眼底检查结果和某些特殊面容如左右耳不对称、眼睑下垂、长人中和嘴角下斜等也呈现出来。结论本文研究结果扩展了CHD4基因变异谱,并丰富了SIHIWES的临床表型谱。     

A missense variant,p.(Ile269Asn), in MC4R as a secondary finding in a child with BCL11A-related intellectual disability

We describe a three year old female who underwent clinical exome sequencing and was diagnosed with BCL11A-related intellectual disability/Dias-Logan syndrome due to a de novo, heterozygous variant in the BCL11A gene, NM_018014.3:c.148C > T; p.(Gln50*). A missense variant in MC4R, NM_005912.3:c.806T > A; p.(Ile269Asn), was also reported as a secondary finding. In her family, her father, paternal aunt, and paternal uncle were all reported to have height and weight measurements suggestive of Class 3 obesity with BMI>40 kg/m². The MC4R gene is not currently listed among those recommended for reporting of secondary findings by the American College of Medical Genetics and Genomics (ACMG). The identification of genetic risk factors for obesity is an emerging field without established guidelines for the care of patients who are found to have a predisposing genetic variant for obesity as a secondary finding. Management suggestions include interventions for weight-management, early screening for obesity-related co-morbidities, such as diabetes and dyslipidemia, and targeted therapies, such as MC4R agonists.     

A maternal de novo non-reciprocal translocation results in a 6q13-q16 deletion in one offspring and a 6q13-q16 duplication in another

Here we report a case of two siblings with reciprocal aberrations, one presenting with a deletion and the other carrying two novel duplications at 6q13q16.1. Interestingly, both alterations were inherited from a healthy mother carrying a non-reciprocal translocation of 6q13q16 to 15q11. Deletions at 6q13q16.1 have been previously described; however this is the first characterisation of a 6q13q16.1 duplication. In this report we provide a comprehensive molecular and phenotypical characterisation of the affected siblings and discuss the profiles of previously identified patients carrying 6q deletions.     

Clinical and Molecular Aspects of MBD5-Associated Neurodevelopmental Disorder (MAND)

MBD5-associated neurodevelopmental disorder (MAND) is an umbrella term that describes a group of disorders, 2q23.1 deletion syndrome, 2q23.1 duplication syndrome, and MBD5 variants, that affect the function of methyl-binding domain 5 (MBD5) and share a common set of neurodevelopmental, cognitive, and behavioral impairments. This review provides a comprehensive clinical and molecular synopsis of 2q23.1 deletion syndrome. Approaches to diagnosis, genetic counseling, and up-to-date management are summarized, followed by a discussion of the molecular and functional role of MBD5. Finally, we also include a brief summary of MBD5 variants that affect function of MBD5 and 2q23.1 duplication syndrome.     

Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals

Loss of function mutations in CTNNB1 have been reported in individuals with intellectual disability [MIM #615075] associated with peripheral spasticity, microcephaly and central hypotonia, suggesting a recognisable phenotype associated with haploinsufficiency for this gene. Trio based whole exome sequencing via the Deciphering Developmental Disorders (DDD) study has identified eleven further individuals with de novo loss of function mutations in CTNNB1. Here we report detailed phenotypic information on ten of these. We confirm the features that have been previously described and further delineate the skin and hair findings, including fair skin and fair and sparse hair with unusual patterning.     

ZDHHC9 X-linked intellectual disability: Clinical and molecular characterization

The ZDHHC9 gene encodes the Zinc Finger DHHC-Type Containing 9 protein that functions as a palmitoyltransferase. Variants in this gene have been reported as the cause of Raymond-type X-linked intellectual disability with only 16 families described in the literature. This study reviews molecular and clinical data from previously reported patients and reports the case of a 13-year-old patient with a splicing variant in ZDHHC9 presenting intellectual disability, developmental delay, facial dysmorphisms, and skeletal defects. Although intellectual disability and developmental delay with severe speech delay have been reported in all cases with available clinical data, the remaining clinical signs differ significantly between patients. Missense, nonsense, frameshift, and splicing variants, in addition to large exonic deletions, have been described suggesting a loss of function mechanism. Though variants are distributed in almost all exons, most missense and nonsense variants affect arginine residues located in the cytoplasmic domains of this transmembrane protein, suggesting possible mutational hotspots.     

Novel GNB1 de novo mutation in a patient with neurodevelopmental disorder and cutaneous mastocytosis: Clinical report and literature review

De novo monoallelic mutations in the GNB1 gene, encoding a β subunit of heterotrimeric G proteins, cause a newly recognized disorder with the typical clinical picture of severe developmental delay/intellectual disability, hypotonia and extrapyramidal symptoms. We describe another case of the condition with manifestations of cutaneous mastocytosis associated with a novel do novo mutation GNB1NM_001282539.1: c.230G > T; p.(Gly77Val). We also present the detailed clinical and etiopathogenetic discussion on previously diagnosed patients as well as suggestions for the link of the mutation with skin disease.     

Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly

Truncating mutations of the BRWD3 gene have been reported in two distinct families with in total four patients so far. By using array-CGH, we detected a 74 Kb de novo deletion encompassing exons 11 through 41 of BRWD3 at Xq21.1 in a 20 year old boy presenting with syndromic intellectual disability. In addition, by using exome sequencing, we ascertained a family with a BRWD3 nonsense mutation, p.Tyr1131*, in four males with intellectual disability. We compared the clinical presentation of these five patients to that of the four patients already described in the literature for further delineation of the clinical spectrum in BRWD3-related intellectual disability. The main symptoms are mild to moderate intellectual disability (n = 9/9) with speech delay (n = 8/8), behavioral disturbances (n = 7/8), macrocephaly (n = 7/9), dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6), and skeletal symptoms (n = 7/7) like pes planus, scoliosis, kyphosis and cubitus valgus.