OBJECTIVE:To elucidate the clinical phenotype and molecular genetic characteristics of intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities (MRD50) due to variants of NAA15 gene. METHODS:A retrospective analysis was carried out on the clinical data of four MRT50 pedigrees (7 patients in total) diagnosed at the Children's Hospital of Nanjing Medical University between February 2022 and August 2024. Pathogenic variants carried by the patients were screened through whole exome sequencing and validated by Sanger sequencing in the respective pedigrees. Bioinformatics tools including MaxEntScan, dbscSNV, RDDC, and SpliceAI were employed to predicted the pathogenicity of splice-site variants. The functional impact of the c.692-5A>G splice-site variant was assessed by reverse transcription-PCR (RT-PCR) combined with agarose gel electrophoresis. PyMOL software was used to predict three-dimensional conformational changes of the variant proteins. Additionally, quantitative real-time PCR (qPCR) was applied to determine the mRNA expression of the NAA15 gene in the peripheral blood sample from the patients. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 202402022-1). RESULTS:The patients (3 males and 4 females), with a last follow-up age ranging from 5-year-and-1-month-old to 35 year old, exhibited varying degrees of intellectual disability, language delay, and learning difficulties. Among them, 3 cases were accompanied by motor developmental delay, 1 case by seizure onset, 1 case by attention-deficit/hyperactivity disorder, 1 case by autism spectrum symptoms, and 1 case by ventricular septal defect. Genetic testing has identified four heterozygous variants in the NAA15 gene, including one case with c.822_823insTA (p.E275*) nonsense variant, two cases with c.376_379delCAAAinsTCCTTACTACAGGT (p.Q126Sfs*9) frameshift variant caused by a complex indel, three cases with c.1029_1038delAGAGTTAGTA (p.E344*) nonsense variant, and one case with a c.692-5A>G splice-site variant. Functional analysis demonstrated that all variants has led to protein truncation. The c.692-5A>G variant may cause aberrant splicing. And the expression level of NAA15 mRNA in patients with the c.692-5A>G variant was significantly lower than the healthy controls. CONCLUSION:Variants of the NAA15 gene, including c.822_823insTA (p.E275*), c.376_379delCAAAinsTCCTTACTACAGGT (p.Q126Sfs*9), c.1029_1038delAGAGTTAGTA (p.E344*), and c.692-5A>G, may lead to MRD50. The core clinical manifestations are intellectual disability and language developmental delay, frequently accompanied by behavioral abnormalities and motor dysfunction.

Biallelic TENM3 variants were recently reported to cause non-syndromic microphthalmia with coloboma-9 (MCOPCB9) and microphthalmia and/or coloboma with developmental delay (MCOPS15). To date, only eight syndromic and non-syndromic microphthalmia cases with recessive TENM3 variants have been reported. Herein, we report two unrelated new cases with biallelic variants in TENM3, widening the molecular and clinical spectrum. Regarding patient 1, WES revealed compound heterozygous variants in the TENM3 gene: c.3847_3855del; p.Leu1283_Ser1285del and c.3698_3699insA; p.Thr1233Thrfs*20 in the index patient, who was presenting with bilateral microphthalmia, congenital cataract, microcephaly, and global developmental delay. Regarding patient 2, compound missense heterozygous variants in the TENM3 gene were identified: c.941C > T; p.Ala314Val and c.6464T > C; p.Leu2155Pro in the 3-year-old boy, who presented with congenital esotropia, speech delay, and motor developmental delay. The clinical features of these two cases revealed high concordance with the previously reported cases, including microphthalmia and developmental delay. The presence of microcephaly in our patient potentially expands the neurologic phenotype associated with loss of function variants in TENM3, as microcephaly has not previously been described. Furthermore, we present evidence that missense variants in TENM3 are associated with similar, but milder, ocular features.

BackgroundSpastic paraplegia type 54 (SPG54) is a rare inherited autosomal recessive disorder, and a complex hereditary spastic paraplegia (HSP) caused by mutations in the phospholipase DDHD2 gene. SPG54 is characterized by early onset of spastic paraplegia, intellectual disability and dysplasia of corpus callosum. Case presentationWe report a 9 years and 5 months old Chinese girl with progressive spasm of the lower limbs, muscle weakness and intellectual disability. Brain magnetic resonance imaging (MRI) showed periventricular leukomalacia and thinning of the corpus callosum. According to the Wechsler Intelligence Scale, her IQ is 42. By whole exome sequencing, novel compound heterozygous missense mutations in the DDHD2 gene [c.168G>C, p.(Trp56Cys) and c.1505T>C, p.(Phe502Ser)] were identified in the proband. Comparative amino acid sequence alignment across different species revealed that Trp56 and Phe502 in the DDHD2 protein were highly conserved during evolution. And multiple in silico prediction tools suggested that both mutations were deleterious. ConclusionsOur study reports a very rare case of complicated HSP caused by two novel compound heterozygous mutations in the DDHD2 gene. Our findings expand the genetic spectrum of SPG54.

Clinical data of a child diagnosed as Gillespie syndrome in the Department of Rehabilitation, Children′s Hospital of Nanjing Medical University in November 2019 were retrospectively analyzed.The 6-month-old boy presented psychomotor retardation, muscular hypotonia, photophobia, nystagmus and inability to focus and follow objects.Slit lamp examination of eyes revealed fixed dilation pupils, bilateral partial aniridia and characteristic iris strands.Genome sequencing and bioinformatics analysis showed a heterozygous splicing mutation in intron 26 of ITPR1 gene, c.3256-1G>A, which was a newly identified pathogenic mutation that was not been reported yet.Moreover, pa-rents of this case did not carry this mutation.It is suggested that Gillespie syndrome should be considered in children with bilateral partial aniridia, psychomotor retardation and muscular hypotonia.Genetic sequencing is helpful for early diagnosis.

Background Interstitial deletions of chromosome band 10q11-q22 was a genomic disorder distinguished by developmental delay, congenital cleft palate and muscular hypotonia. The phenotypes involved were heterogeneous, hinge on the variable breakpoints and size. Case presentation Here, we presented a patient with soft palate cleft, growth and development delay. The patient was a 2 years and 5 months girl who was not able to walk unless using a children’s crutches to support herself. Whole-exome sequencing (WES) and whole-genome mate-pair sequencing (WGMS) were both performed by next generation sequencing (NGS). A 20.76 Mb deletion at 10q11.23q22.1 (seq[GRCh37/hg19]del(10)(50,319,387-71,083,899) × 1) was revealed by the WGMS, which was verified as de novo by quantitative polymerase chain reaction (QPCR). Conclusion Children with 10q11-q22 deletions greater than 20 MB have never been reported before, and we are the first to report and provide a detailed clinical phenotype, which brings further knowledge of 10q11-q22 deletions.

Abstract Background The Raynaud-Claes type of X-linked syndromic mental retardation (MRXSRC) is a very rare condition, by intellectual disability ranged from borderline to profound, impaired language development, brain abnormalities, facial dysmorphisms and seizures. MRXSRC is caused by variants in CLCN4 which encodes the 2Cl−/H+ exchanger ClC-4 prominently expressed in brain. Case presentation We present a 3-year-old Chinese girl with intellectual disability, dysmorphic features, brain abnormalities, significant language impairment and autistic features. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, a mega cisterna magna and ventriculomegaly. Whole exome sequencing (WES) was performed to detect the molecular basis of the disease. It was confirmed that this girl carried a novel heterozygous missense variant (c.1343C > T, p.Ala448Val) of CLCN4 gene, inherited from her mother. This variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. Conclusion Our investigation expands the phenotype spectrum for CLCN4 variants with syndromic X-linked intellectual disability, which help to improve the understanding of CLCN4-related intellectual disability and will help in genetic counselling for this family.

目的 探讨ARID1B基因变异致Coffin-Siris综合征的临床及遗传特征.方法 回顾分析1例ARID1B基因变异致Coffin-Siris综合征患儿的临床资料及分子遗传学检测结果,并复习相关文献.结果 患儿,男,2岁8个月,因智力运动发育落后就诊.患儿生后就有喂养困难,体质量增长不良,特殊面容(头皮毛发稀疏、发际低、拱形浓眉、长睫毛、鼻翼宽、鼻梁低、上唇薄、下唇厚而外翻、唇毛明显),四肢肌张力低下,右足趾甲小.全外显子测序显示ARID1B基因存在c.6257T>C(p.Leu 2086 Pro)杂合错义变异,父母未发现上述变异,为新生变异.文献共检索到已报道因ARID1B基因所致Coffin-Siris综合征患者86例,患儿临床特征与已报道病例基本相符.结论 Coffin-Siris综合征为罕见的常染色体显性遗传病,可累及多个系统,基因检测可协助诊断.

OBJECTIVE:To explore the clinical features and genetic characteristics of a child with 5q14.3 microdeletion syndrome.METHODS:Whole exome sequencing (WES) and low-coverage massively parallel copy number variation sequencing (CNV-seq) were used to determine the potentially pathogenic variants as well as the copy number variations (CNVs). Candidate CNVs were verified by real-time fluorescence quantitative PCR.RESULTS:The patient presented with psychomotor retardation, epilepsy, peculiar face and hypotonia. The results of WES suggested that he has carried a heterozygous deletion for chr5:86 564 268-88 119 605. CNV-seq indicated that the patient carried a heterozygous deletion of 4.76 Mb heterozygous deletion on chromosome 5q14.3. The MEF2C gene and RASA1 gene in the deletion area were verified by real-time fluorescence quantitative PCR. The results showed that the MEF2C geneand RASA1 gene were heterozygous deletion, which was consistent with the sequencing results.CONCLUSION:The child was diagnosed with 5q14.3 microdeletion syndrome. Haploinsufficiency of the MEF2C gene may underlie the manifestations of 5q14.3 microdeletion syndrome.

目的 探讨Wolf-Hirschhorn综合征(WHS)临床特征及基因突变.方法 回顾分析2017-11-20-2018-05-26南京医科大学附属儿童医院收治的4例发育延迟及智力低下患儿的临床资料,临床拟诊为WHS.应用染色体微阵列芯片分析技术进行基因检测,并复习相关文献总结疾病特点.结果 2例男性和2例女性患儿因生后特殊面容(希腊头盔样面容)、智力低下、发育延迟、肌张力低下、癫痫,应用染色体微阵列芯片分析技术发现患儿4p16.3区域2.24～3.8 Mb的缺失,确诊WHS,给予抗癫痫及康复治疗并定期随访.结论 尽早完善染色体芯片技术检查有助于早期诊断WHS,且能判断预后.染色体微阵列芯片分析与传统细胞遗传学分析方法相比,具有高分辨和高准确度的优点,可为产前遗传学诊断提供更详细信息.

Objective:To detect the mutations of the ALDH3A2 gene in 2 families of patients with Sj?gren-Larsson syndrome(SLS), and to guide their parents to be pregnant rationally. Methods:Two SLS children admitted to Children′s Hospital of Nanjing Medical University were clinically researched and analyzed of their ALDH3A2 gene mutations, comprehensive rehabilitation treatment, and systematic review.The clinical studies of 16 children and 8 cases of ALDH3A2 gene mutation sites that have been reported in China so far were analyzed in order to provide theoretical basis for early diagnosis, treatment, genetic counseling, and prenatal diagnosis. Results:The 2 children in this study had typical ichthyosis-like skin changes, spastic diplegia or quadriplegia, and cannot walk independently, combined with mental retardation and delayed language development.The patients′s ALDH3A2 gene changed, and both their parents and unaffected sister were heterozygous carriers of the mutation. Conclusions:The detection of the ALDH3A2 gene in suspicious SLS patients works well in early diagnosis, rehabilitation treatment, and can improve curative effect.At the same time it is more meaningful to guide genetic counseling and prenatal diagnosis.

Sj(o)gren-Larsson综合征(SLS)是一种罕见的常染色体隐性遗传性神经皮肤综合征,临床表现主要包括先天性鱼鳞病、精神发育落后、双侧或四肢痉挛性瘫痪三联征.我国迄今报道10余例,其中相关基因报道较少,现对南京医科大学附属儿童医院康复科收治的1例SLS患儿家系进行ALDH3A2基因突变研究,探讨此病临床表现与基因的关系.

Objective To explore the clinical features and the gene mutations in MECP 2 duplication syndrome. Methods The clinical data of a child with developmental retardation and hypophrenia accompanied with respiratory tract infection was analyzed retrospectively. Microarray analysis technique was used to detect the genes in the patient and his family. The pertinent literature was reviewed. Results A 1-year and 7-month old boy was found to have hypotonia, developmental delay, and recurrent respiratory tract infections after birth. Microarray analysis showed a duplication of 441.88kb in Xq28 area and diagnosis of MECP2 duplication syndrome was confirmed. His grandmother, mother, and two aunts were found duplication of 441.73-441.88kb in Xq28 area, all of whom were MECP2’s female carrier. Conclusions The improvement of chromosome chip technology inspection is helpful to the early diagnosis of MECP2 duplication syndrome.

先天性代谢异常(inbom errors of metabolism)包括氨基酸、有机酸、糖、脂肪、激素等多种代谢缺陷,系由于遗传性代谢途径缺陷,导致异常代谢物的蓄积或生理必需物质的缺乏.一些先天性代谢异常临床表现缺乏特异性,早期诊断存在一定困难.近几年,随着尿气相色谱-质谱法(CC/MS法)的临床应用,使既往许多易漏诊的先天性代谢异常得到了早期诊断.本研究对我院康复科住院的34例无脑瘫的三大主要致病高危因素(窒息、早产、黄疸)的脑瘫儿童进行了先天性代谢异常的筛查,现将结果报道如下.