Possible genes responsible for developmental delay observed in patients with rare 2q23q24 microdeletion syndrome: Literature review and description of an additional patient

Cases of 2q23q24 microdeletion syndrome are rare. Patients with chromosomal deletions in this region often show language impairment and/or developmental delay of variable severity. Previous genotype–phenotype correlation study suggested GALNT13 and KCNJ3 as possible candidate genes for such phenotypes. We identified a new overlapping deletion in a patient with severe developmental delay. The identified deletion extended toward the distal 2q24.1 region, and more severe phenotypes in the present patient were considered to be related to the additionally deleted genes including NR4A2 and GPD2. Previously reported chromosomal translocation and the mutation identified in GPD2 suggested that this gene would be responsible for the developmental delay. Re‐evaluation for the critical region for behavior abnormalities commonly observed in the patients with overlapping deletions of this region suggested that KCNJ3 rather than GALNT13 may be responsible for abnormal behaviors, although there was phenotypic variability. Combinatory deletions involving KCNJ3 and GPD2 may lead to more severe developmental delay. Further studies would be necessary to establish clearer genotype–phenotype correlation in patients with 2q23q24 microdeletion syndrome.     

4q34.1–q35.2 deletion in a boy with phenotype resembling 22q11.2 deletion syndrome

Small terminal or interstitial deletions involving bands 4q34 and 4q35 have been described in several patients with a relatively mild phenotype such as mild to moderate intellectual disability and minor dysmorphic features. We present a boy born from unrelated parents with a de novo 4q34.1–q35.2 deletion and clinical features resembling 22q11.2 deletion syndrome. To the best of our knowledge, this is the first reported patient with 4q34–q35 deletion and phenotype resembling 22q11.2 deletion syndrome without fifth finger anomalies as a specific feature of 4q- syndrome. G-banding karyotyping disclosed the deletion, which was further delineated by microarray comparative genomic hybridization. Fluorescence in situ hybridization and multiplex ligation-dependent probe amplification analyses did not reveal rearrangements of 22q11.2 region. MLPA confirmed the deletion within the 4q35.2 region. Conclusion: Given the considerable clinical overlaps between the 22q11.2 deletion syndrome and clinical manifestation of the patient described in this study, we propose that region 4q34.1–q35.2 should be considered as another region associated with phenotype resembling 22q11.2 deletion syndrome. We also propose that distal 4q deletions should be considered in the evaluation of patients with phenotypic manifestations resembling 22q11.2 deletion syndrome in whom no 22q11.2 microdeletion was detected, even in the absence of distinctive fifth finger anomalies. Additionally, we underline the importance of applying array CGH that enables simultaneous genome-wide detection and delineation of copy number changes (e.g., deletions and duplications).     

22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes.

A microdeletion of chromosome 22q11.2 is found in most patients with velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome, and in some patients with Cayler cardiofacial and autosomal dominant Opitz-G/BBB syndromes. A wide spectrum of clinical findings accompanies the 22q11.2 deletion, without genotype or phenotype correlation even among affected family members. Classic features are dysmorphic facies, conotruncal cardiac defects, hypocalcemic hypoparathyroidism, T-cell mediated immune deficiency, and palate abnormalities. Less well recognized are learning, speech, feeding, and psychiatric disorders, and renal and musculoskeletal defects. Parathyroid and immune deficiencies in the same individual can progress or resolve with time. The 22q11.2 deletion can be inherited as an autosomal dominant or arise as a de novo deletion or translocation. Fluorescent in situ hybridization using cosmid probes mapping to the DiGeorge chromosomal region is a widely available method to detect the 22q11.2 deletion in metaphase chromosomes from cultured lymphocytes, amniocytes, or chorionic villi. The ubiquitin-fusion-degradation-1-like gene, expressed in embryonic branchial arches and in the conotruncus, appears to play a prominent role in the pathogenesis of the 22q11.2 deletion syndrome.     

15q11.2-13.2微重复四倍体综合征1例并文献复习

目的 采用分子遗传学技术分析1例常规染色体核型拟诊为21/22三体的发育迟缓伴孤独症患儿,明确遗传学诊断。方法 收集患儿及其父母的外周血标本,常规提取基因组DNA,应用高分辨染色体核型分析（400-550带）检测患儿及其父母的染色体数目及结构,微阵列比较基因组杂交技术(array-CGH)筛查患儿的全基因组拷贝数变异,以荧光原位杂交技术（FISH）对异常的基因拷贝进行染色体精确定位和定量。结果 女,2岁,发育迟缓伴孤独症样表现。外侧眼角下垂、内眦赘皮。常规染色体核型检查（320带）分别为47,XX,+22和47,XX,+21。高分辨染色体核型分析显示,该患儿携带额外标记染色体（SMC）,核型为47,XX,+mar dn,尚不能确定是否为21/22三体携带者,患儿父亲高分辨率核型染色体分析提示为46,XY,母亲为46,XX,提示患儿携带SMC为新生突变。array-CGH检测显示15q11.2-13.2区域微重复（chr15:22684529-30730543,8.0 Mb,hg19）。FISH验证该SMC来源于15号染色体,由15q11.2-13.2区域二倍体及双着丝粒组成。患儿最终诊断为15q11.2-13.2微重复四倍体综合征。复习文献报道的15q11.2-13.2拷贝数增加病例的临床表型,微重复四倍体综合征的主要表型有智力低下/发育迟缓（100％）、肌张力低下（92.9％）、孤独症/孤独症样表现（71.4％）和癫痫（61.5％）等。结论 15q11.2-13.2微重复四倍体综合征是患儿发生精神发育迟滞伴孤独症的遗传学基础,array-CGH能够快速、准确地检测基因组的微小失衡。     

A new case of an interstitial deletion (4)(q25q27) characterised by molecular cytogenetic techniques and review of the literature

Interstitial deletions of the long arm of chromosome 4 involving the region 4q25-q27 are rare. Clinical features of patients carrying such a deletion include craniofacial and skeletal anomalies, malformations of the eye, cardiac abnormalities, congenital hypotonia, and developmental retardation. Here we report a new case of a de novo interstitial deletion 4(q25q27) in a girl with congenital malformations and findings of Rieger syndrome. The abnormal chromosome 4 was characterised by G-banding and molecular cytogenetic methods including comparative genomic hybridisation and two-colour fluorescent in situ hybridisation with band-specific probes. CONCLUSION: this report highlights the importance of high quality banding and fluorescent in situ hybridisation analyses to screen for subtle chromosome 4q25-q27 aberrations in patients with clinical features of Rieger syndrome.     

Unusual features in children with inv dup(15) supernumerary marker: a study of genotype-phenotype correlation in Taiwan

Recent molecular cytogenetic studies have elucidated the origin and nature of extra structurally abnormal chromosomes (ESACs) or small supernumerary chromosomes, which are often associated with developmental delay and malformations. We studied the prevalence of inv dup(15) in a nationwide screening programme for mentally retarded children in Taiwan and tried to correlate the genotype and phenotype in those patients. Fluorescence in situ hybridization (FISH) analysis using D15Z, D15Z1, and the cosmids from the Prader-Willi/Angelman syndrome chromosome region (PW/ASCR) was performed on 54 patients (0.45%) with ESACs from 11893 probands within a 5-year period. Of them, inv dup(15) was confirmed in 25 children (46.3%) by FISH analysis. The PW/ASCR probes were used to clarify the size and DNA composition of the markers. Patients with inv dup(15) chromosomes, containing only the heterochromatin or little euchromatin of the proximal 15q (i.e., pter→q11:q11→pter) may have a rather mild or nearly normal phenotype (group 1). Only one patient had some features suggestive of Angelman syndrome, but was considered to be a result of deleted (15)(q12) in the chromosome 15 homologue. Additional copies within D15S11 through GABRB3 (15q11.2-13) resulted in an abnormal phenotype which involved mental and developmental delay but was different from the classical phenotype of PW/AS (groups 2, 3). Signs of autistic behavior did occur in each group. FISH combined with microsatellite analyses showed that the marker was often of maternal origin in de novo cases (n = 12, 86%), or inherited from the mother in only one familial case. Down-inv dup(15) was mentioned in two cases. Unusual features including diaphragmatic eventration, hyperlaxity of joints, arachnodactyly, brain atrophy, epilepsy (particularly infantile spasm), ataxia, genital abnormalities, and cleft lip/palate were noted in those patients. This observation expands the range of phenotypic expression associated with this relatively common ESAC. Conclusion Marked phenotypic diversities exist in children with inv dup(15), dependent upon the size or genetic composition of the markers, degree of mosaicism, parental origin and familial occurrence or not. Patients with a larger inv dup(15) marker chromosome including the PW/ASCR may have a higher risk of abnormalities, but not the typical Prade-Willi/Angelman syndrome phenotype. Received: 11 February 1997 and in revised form: 20 May 1997 / Accepted: 20 May 1997     

6p subtelomere deletion with congenital glaucoma,severe mental retardation,and growth impairment

Submicroscopic deletion of the 6p subtelomere has recently been recognized as a clinically identifiable syndrome. A distinct phenotype has emerged consisting of developmental delay/mental retardation, language impairment, hearing loss, and ophthalmologic, cardiac, and craniofacial abnormalities, including hypertelorism, midface hypoplasia, small nose, and high arched palate. We describe here a patient with 6p subtelomere deletion associated with congenital glaucoma, severe mental retardation, and growth impairment. Fluorescent in situ hybridization analysis revealed only one 6p25.3 signal. Array comparative genomic hybridization assay showed 2.1 Mb deletion and 4.14 Mb duplication in the 6p25 region. Generally, developmental delay and language impairment are common findings in patients with 6p subtelomere deletion syndrome, but growth impairment is not. Compared to that, the present patient showed atypically severe developmental delay and growth impairment.     

De novo terminal deletion of chromosome 7 [46, XX, del(7)(q35)]

Objective : To report a new case of de novo 7q deletion distal to q35.
Methodology : Developmental, cytogenetic and audiological investigations were carried out in the assessment of this rare chromosomal condition.
Results : Moderate developmental delay, mild congenital microcephaly, growth retardation and conductive hearing impairment were found for this case of 46, XX, del(7)(q35).
Conclusions : The phenotype of 7q terminal deletion is highly variable.     

16q12 microdeletion syndrome in two Japanese boys

Microdeletion of 16q12 is a rare chromosomal abnormality. We present the cases of two Japanese patients with developmental and renal symptoms of differing clinical severity. Both patients had 16q12 interstitial microdeletions that included the entire SALL1 gene. Patient 1 was a 15‐year‐old Japanese boy clinically diagnosed with branchio‐oto‐renal syndrome with mild developmental delay, but with no imperforate anus or polydactyly. Array comparative genome hybridization (aCGH) indicated a 5.2 Mb deletion in 16q12, which included SALL1. Patient 2 was a 13‐year‐old Japanese boy diagnosed with Townes–Brocks syndrome and severe developmental delay, epilepsy, and renal insufficiency requiring renal replacement therapy. Fluorescence in situ hybridization indicated deletion of the entire SALL1 gene. Subsequent aCGH showed a 6 Mb deletion in 16q12q13, which included SALL1. Precise analysis of the present two cases will give us some clues to elucidate the pathogenic mechanisms of 16q12 microdeletion syndrome.     

Hypocalcemia impacts heart failure control in DiGeorge 2 syndrome

Chromosome 10p terminal deletion accounts for a rare subset among patients presenting with DiGeorge syndrome, and is designated as DiGeorge 2 syndrome. We report a neonate with DiGeorge-like phenotype having a deletion of distal 10p (p13-pter) and a duplication of terminal 3q (q29-qter) derived from paternal balanced translocation between 3q29 and 10p13. She had facial dysmorphism, atrial and ventricular septal defect, impaired T-cell function, hypoparathyroidism, sensorineural hearing loss, renal abnormalities and developmental delay. Her phenotype corresponded well with the typical characteristics of partial monosomy 10p and the small duplication of terminal 3q did not involve the critical region of 3q duplication syndrome. Clinically, hypoparathyroidism-related hypocalcemia lasted for three weeks and resulted in repeated episodes of heart failure. It was not until the calcium level was normalized that her heart failure improved markedly.
Conclusion: Cytogenetic analysis can help to recognize patients early on who have terminal 10p deletion when microdeletion of 22q11.2 is not the cause of DiGeorge syndrome. Hypoparathyroidism-related hypocalcemia impacts heart failure control in partial monosomy 10p and should be managed aggressively on critical care.     

染色体15q11.2和15q13.3区域的微缺失与中国儿童失神癫的相关性

目的探讨15q11.2和15q13.3区域的拷贝数变异(CNV)是否与中国汉族儿童失神癫(CAE)患儿的表型相关。方法采用Affymetrix SNP 5.0芯片技术对198例CAE患儿和198名北方汉族健康成人进行特发性全面性癫(IGEs)相关的CNV检测,对发现的阳性CNV采用高密度寡核苷酸为基础的比较基因组杂交芯片技术进一步验证。应用Accucopy技术对另外200例CAE患儿进行15q11.2和15q13.3区域的CNV检测。结果通过Affymetrix SNP 5.0芯片技术在198例CAE患儿中发现3例存在15q11.2的微缺失,1例存在15q13.3的微缺失,而在198名健康对照中没有发现。另外200例CAE患儿中发现1例存在15q11.2的微缺失。发现的5例微缺失中除1例为新发CNV外,余4例均遗传自母亲,这些患儿的母亲没有发现明确的癫表现。结论15q11.2和15q13.3的微缺失是CAE患儿重要的疾病相关CNV,并且15q11.2微缺失在中国汉族人群中具有较15q13.3微缺失更高的发生率。     

Mosaic 7q31 deletion involving FOXP2 gene associated with language impairment

We report on a 10-year-old patient with childhood apraxia of speech (CAS) and mild dysmorphic features. Although multiple karyotypes were reported as normal, a bacterial artificial chromosome array comparative genomic hybridization revealed the presence of a de novo 14.8-Mb mosaic deletion of chromosome 7q31. The deleted region involved several genes, including FOXP2, which has been associated with CAS. Interestingly, the deletion reported here was observed in about 50% of cells, which is the first case of mosaicism in a 7q31 deletion. Despite the presence of the deletion in only 50% of cells, the phenotype of the patient was not milder than other published cases. To date, 6 cases with a deletion of 9.1-20 Mb involving the FOXP2 gene have been reported, suggesting a new contiguous gene deletion syndrome characterized mainly by CAS caused by haploinsufficiency of the genes encompassed in the 7q critical region. This report suggests that children found with a deletion involving the FOXP2 region should be evaluated for CAS and that analysis of the FOXP2 gene including array comparative genomic hybridization should be considered in selected patients with CAS. Mosaic deletions in this area may also be considered as causative of CAS.     

Muscular hypotonia, developmental retardation, speech delay and mildly dysmorphic features: 22q13 deletion syndrome (Phelan-McDermid Syndrome) as an important differential diagnosis

BACKGROUND: Clarifying the cause of global developmental and speech delay is of considerable significance in pediatrics. We present the clinical phenotype of the 22q13 deletion syndrome - also known as Phelan-McDermid syndrome - and show the diagnostic options. PATIENT: We report on a female patient with muscular hypotonia, tall stature, minor facial dysmorphism, retarded motor and mental development, and severe speech delay. METHOD: Chromosomal analysis was performed first on peripheral lymphocytes on GTG-banded chromosomes. Fluorescence in situ hybridization (FISH) analysis was carried out using the dual-color LSI DiGeorge/VCFS Region Probe (TUPLE1, N25) (Vysis/Abbott) and the subtelomeric probe tel 22q13.3 (Tel Vysion 22q).Results: The analysis of metaphase chromosomes at 450 band resolution showed a normal female karyotype 46,XX. FISH analysis revealed a 22q13 deletion. CONCLUSION: Muscular hypotonia and developmental delay are non-specific findings observed in many genetic syndromes. In association with severe speech delay and normal or advanced growth pediatricians should consider 22q13 deletion syndrome as a potential cause and initiate a genetic examination.     

Penoscrotal inversion, hypospadias, imperforate anus, facial anomalies, and developmental delay: definition of a new clinical syndrome

 We describe a 2-month-old boy with penoscro- tal inversion, hypospadias, imperforate anus, facial anomalies, developmental retardation, and a subtelomeric deletion of chromosome 13q. His phenotype with anogenital malformations and characteristic facies closely resembled two unrelated patients with minute deletions of chromosome 13q who we reported earlier. In addition, he had unilateral renal agenesis. We propose that these patients represent a clinically recognizable, novel chromosomal microdeletion syndrome. The findings indicate the presence of a major gene(s) on chromosome 13q33.2qter that regulate(s) the migration and development of ano-reno-genital cells and organs. We speculate that mutations of this developmental gene(s) may also result in more frequent congenital malformations (isolated hypospadias, uterus bicornis, unilateral renal agenesis). Additional studies are needed to further delineate the genetic defect. Accepted: 15 September 1999     

A 10q21.3q22.2 microdeletion identified in a patient with severe developmental delay and multiple congenital anomalies including congenital heart defects

Interstitial deletions in the 10q21.3q22.2 chromosomal region are rare. A de novo microdeletion in this region was identified in a patient with severe developmental delay and multiple congenital anomalies, including congenital heart defects. The identified 10.4‐Mb deletion included 84 RefSeq genes. CTNNA3 and JMJD1C have been associated with cardiomyopathy and neurological impairments (autism and/or intellectual disability), respectively. Because there is no gene which shows one‐to‐one relation to clinical features observed in this patient, combinatory deletion of the genes in this region would be causative of the clinical features in this patient.     

Microcephaly, sensorineural deafness and Currarino triad with duplication–deletion of distal 7q

Currarino syndrome (CS) is a peculiar form of caudal regression syndrome [also known as autosomal dominant sacral agenesis (OMIM no. 176450)] characterised by (1) partial absence of the sacrum with intact first sacral vertebra, (2) a pre-sacral mass and (3) anorectal anomalies (Currarino triad). We studied a 3-year-old girl with Currarino triad who had additional systemic features and performed array comparative genomic hybridisation to look for chromosomal abnormalities. This girl had the typical spectrum of anomalies of the CS including (a) partial sacral agenesis (hemisacrum with remnants of only sacral S1–S2 vertebrae and a residual S3 vertebral body) associated with complete coccygeal agenesis, (b) pre-intrasacral dermoid, (c) intra-dural lipoma, (d) ectopic anus and (e) tethered cord. She had, in addition, pre- and post-natal growth impairment (<3rd percentile), severe microcephaly (<?3 SD) with normal gyration pattern and lack of cortical thickening associated with a hypoplastic inferior vermis, facial dysmorphism, sensorineural deafness and decreased serum levels of IGF-1. A de novo 10.3-Mb duplication of 7q34–q35 and an 8.8-Mb deletion on 7q36 were identified in this patient. The Homeobox HLXB9 (CS) gene is contained within the deletion accounting for the CS phenotype including microcephaly. The spectrums of associated abnormalities in the IGF-1 deficiency growth retardation with sensorineural deafness and mental retardation syndrome (OMIM no. 608747) are discussed. To the best of our knowledge, this is the first reported case of a patient with distal 7q chromosomal imbalance and features of CS triad (including microcephaly) and the first documented case of a patient with normal gyration pattern microcephaly. The spectrum of associated anomalies in this newly recognised phenotype complex consists of growth failure, typical facial anomalies with additional (previously unreported) nervous system abnormalities (e.g. sensorineural deafness) and somatomedin C deficiency.     

筛查染色体22q11.2缺失综合征在先天性心血管畸形中的意义

染色体22q11.2缺失综合征(22q111DS)又称DiGeorge综合征、腭-心-面综合征,临床表现极具多样性,可累及心血管、免疫系统、面容、内分泌系统,甚至语言发育、精神等多方面.荧光原位杂交能够检测到染色体22q11.2缺失.目前国内对本病认识尚不足,尚未建立规范的临床筛查体系,确诊率亦低.已报道的22q11D...     

微阵列比较基因组杂交技术对不明原因智力低下/生长发育迟缓患儿的分子诊断

目的　分析不明原因智力低下(ID)和(或)生长发育迟缓(DD)患儿潜在的致病性基因组不平衡, 及其与表型的相关性, 探讨高密度微阵列比较基因组杂交技术(array-CGH)在临床分子遗传学诊断中的应用价值。方法　采用array-CGH技术对16例ID/DD患儿进行全基因组扫描分析, 并用多重连接探针扩增技术(MLPA)对检出的基因组不平衡异位进行验证。结果　16例患儿高分辨G显带核型分析均无异常。6例(38%)患儿存在基因拷贝数异常(CNVs), 其中3例CNVs为正常多态性改变; 1例CNVs涉及4p16.3区域微缺失, 考虑为Wolf-Hirschhorn综合征; 1例CNVs涉及7q11.23区域微缺失, 考虑为Williams-Beuren 综合征; 另1例CNVs临床意义不明确, 包含2个重复突变, 该突变与智力低下、脑发育迟缓、特殊面容、隐睾、牙列不齐等有关, 证实该CNVs具有临床意义。结论 通过array-CGH技术对不明原因ID/DD患儿进行全基因组扫描, 可为部分患儿明确病因诊断。该技术作为一种高通量、快速的疾病研究手段, 在ID/DD的病因诊断中具有重要的临床意义。     

筛查染色体22q11.2缺失综合征在先天性心血管畸形中的意义

染色体22q11.2缺失综合征(22q111DS)又称DiGeorge综合征、腭-心-面综合征,临床表现极具多样性,可累及心血管、免疫系统、面容、内分泌系统,甚至语言发育、精神等多方面.荧光原位杂交能够检测到染色体22q11.2缺失.目前国内对本病认识尚不足,尚未建立规范的临床筛查体系,确诊率亦低.已报道的22q11DS病例中,先天性心血管畸形尤其是圆锥干畸形和主动脉弓畸形发生率很高,也最确切.该文拟综述22q11DS,并分析如何在临床工作中从心血管畸形入手早期发现22q11DS,从而早期干预治疗、综合评估、长期随访及遗传咨询,提高患者及后代生活质量.     

Velocardiofacial syndrome associated with atrophy of the shoulder girdle muscles and cervicomedullary narrowing.

Velocardiofacial syndrome is the most common microdeletion syndrome in humans. It is secondary to a chromosome 22q11 rearrangement and is characterized by craniofacial abnormalities, heart defects and learning disability. We report a case of a 10-year-old girl with a chromosome 22q11 deletion who, in addition to learning difficulties, hypernasal speech and mild dysmorphic features, had weakness and wasting of the shoulder girdle muscles but no cardiac involvement. Brain magnetic resonance imaging revealed narrowing of the cervicomedullary junction. The clinical features of this patient with velocardiofacial syndrome further expand the spectrum of abnormalities associated with this condition.