Clinical utility of an array comparative genomic hybridization analysis for Williams syndrome

To reveal the relation between intellectual disability and the deleted intervals in Williams syndrome, we performed an array comparative genomic hybridization analysis and standardized developmental testing for 11 patients diagnosed as having Williams syndrome based on fluorescent in situ hybridization testing. One patient had a large 4.2‐Mb deletion spanning distally beyond the common 1.5‐Mb intervals observed in 10/11 patients. We formulated a linear equation describing the developmental age of the 10 patients with the common deletion; the developmental age of the patient with the 4.2‐Mb deletion was significantly below the expectation (developmental age = 0.51 × chronological age). The large deletion may account for the severe intellectual disability; therefore, the use of array comparative genomic hybridization may provide practical information regarding individuals with Williams syndrome.     

一例13号环状染色体综合征患儿的临床及遗传学分析

患儿,女,5个月,因生长发育迟缓就诊,体格检查发现体格发育落后,特殊面容（小头畸形、眼距宽、耳位偏低、鼻梁扁平、短人中）以及一侧小阴唇缺失。外周血染色体核型为46,XX,r（13）（p11q33）[82]/45,XX,-13[10]/46,XX,r（13;13）（p11q33;p11q33）[8];微阵列比较基因组杂交（aCGH）检测显示13q11q33.2区域和13q33.2q34区域分别有87.5 Mb的重复和8.2 Mb的缺失;荧光原位杂交（FISH）显示13号环状染色体长臂末端缺失。诊断为13号环状染色体综合征。该综合征临床表型多变,主要与染色体区带中遗传物质丢失的数量、部位以及不同核型嵌合比例不同等密切相关。     

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.     

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.     

Partial monosomy of 10p and duplication of another chromosome in two patients

Partial monosomy of 10p is a rare chromosomal abnormality. Common features are hypoparathyroidism, deafness, renal anomalies, distinctive facies, and mental retardation, with phenotypic variability. We report two patients with chromosomal abnormalities identified on single‐nucleotide polymorphism (SNP) array analysis. Although patient 1 had common features of monosomy10p, G‐banding indicated a normal karyotype. SNP array and fluorescence in situ hybridization (FISH), however, indicated unbalanced translocation of a 10p terminal deletion of 11.7 Mb and a 15q terminal duplication of 8.2 Mb. In patient 2, SNP array and FISH indicated a 10p terminal deletion of 12.6 Mb and a 7q terminal duplication of 1.9 Mb. This is the first case report of monosomy 10p combined with trisomy 15q (patient 1). Because the clinical heterogeneity of the 10p deletion syndrome would be affected by duplication of another chromosome, we emphasize that SNP/microarray analysis is necessary to confirm genotype–phenotype correlation.     

15Q11.2 (BP1-BP2) microdeletion, a new syndrome with variable expressivity

The case of a boy with psychomotor retardation and dysmorphic features is presented. He has a 1.5 Mb 15q11.2 microdeletion of paternal origin diagnosed by aCGH. The deletion is located between breakpoints BP1 and BP2 of the Prader-Willi/Angelman syndromes critical region. Clinical features in our patient fit well with those described in ten cases of pure BP1-BP2 deletion published to date.     

11p15 duplication and 13q34 deletion with Beckwith–Wiedemann syndrome and factor VII deficiency

Here we report a patient with 11p15.4p15.5 duplication and 13q34 deletion presenting with Beckwith–Wiedemann syndrome (BWS) and moderate deficiency of factor VII (FVII). The duplication was initially diagnosed on methylation‐sensitive multiplex ligation‐dependent probe amplification. Array comparative genome hybridization confirmed its presence and indicated a 13q34 distal deletion. The patient's clinical symptoms, including developmental delay and facial dysmorphism, were typical of BWS with paternal 11p15 trisomy. Partial 13q monosomy in this patient is associated with moderate deficiency of FVII and may also overlap with a few symptoms of paternal 11p15 trisomy such as developmental delay and some facial features. To our knowledge this is the first report of 11p15.4p15.5 duplication associated with deletion of 13q34 and FVII deficiency. Moreover, this report emphasizes the importance of detailed clinical as well as molecular examinations in patients with BWS features and developmental delay.     

Natural histories of patients with Wolf‐Hirschhorn syndrome derived from variable chromosomal abnormalities

Wolf‐Hirschhorn syndrome (WHS) is a subtelomeric deletion syndrome affecting the short arm of chromosome 4. The main clinical features are a typical craniofacial appearance, growth deficiency, developmental delays, and seizures. Previous genotype‐phenotype correlation analyses showed some candidate regions for each clinical finding. The WHS critical region has been narrowed into the region 2 Mb from the telomere, which includes LETM1 and WHSC1; however, this region is insufficient to cause “typical WHS facial appearance”. In this study, we identified 10 patients with a deletion involving 4p16.3. Five patients showed pure terminal deletions and three showed unbalanced translocations. The remaining patients showed an interstitial deletion and a suspected inverted‐duplication‐deletion. Among 10 patients, one patient did not show “typical WHS facial appearance” although his interstitial deletion included LETM1 and WHSC1. On the other hand, another patient exhibited “typical WHS facial appearance” although her small deletion did not include LETM1 and WHSC1. Instead, FGFRL1 was considered as the candidate for this finding. The largest deletion of 34.7 Mb was identified in a patient with the most severe phenotype of WHS.     

A further case of the recurrent 15q24 microdeletion syndrome,detected by array CGH

We report on a 10-year-old patient with developmental delay, craniofacial dysmorphism, digital and genital abnormalities. In addition, muscular hypotonia, strabism, and splenomegaly were observed; inguinal and umbilical hernias were surgically corrected. Mucopolysaccharidoses and CDG syndromes could not be found. Chromosome analysis revealed a normal male karyotype (46,XY). A more detailed investigation of the patient's genomic DNA by microarray-based comparative genomic hybridization (array CGH) detected an interstitial 3.7 Mb deletion ranging from 15q24.1 to 15q24.3 which was shown to be de novo. Interstitial deletions involving 15q24 are rare. Sharp et al. (Hum Mol Genet 16:567-572, 2007) recently characterized a recurrent 15q24 microdeletion syndrome with breakpoints in regions of segmental duplications. The de novo microdeletion described here colocalizes with the minimal deletion region of the 15q24 microdeletion syndrome. The distinct clinical phenotype associated with this novel microdeletion syndrome is similar to the phenotype of our patient with respect to specific facial features, developmental delay, microcephaly, digital abnormalities, and genital abnormalities in males. We present a genotype-phenotype correlation and comparison with patients from the literature.     

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.     

16p11.2缺失综合征1例并文献复习

目的 提高对16p11.2缺失综合征的临床和基因特征的认识。方法 总结分析1例16p11.2缺失综合征患儿的临床发现、辅助检查、诊断和随访资料,并文献复习。结果 ①患儿,男,2月13 d,因“发热近20 d伴咳嗽、腹泻”起病。入院查体可见右手六指畸形,脊柱侧弯,外周血淋巴细胞及其亚群明显低于正常同龄儿。X线胸片示胸椎9～12部分椎体呈半椎体畸形,胸骨塑形异常。予抗感染等治疗后好转,并呈多动兴奋表现。出院后随访提示淋巴细胞数量较住院时好转,但WBC、中性粒细胞及CD4+T细胞均低于正常值。患儿5月龄时诊断癫,予抗癫药物治疗有效。应用染色体芯片检测技术,并采用高密度寡核苷酸微阵列比较基因组杂交技术证实16p11.2区域缺失,缺失片段大小约0.545 4 Mb,该区段所包含的基因有SPN、QPRT、 C16orf54、 KIF22、 MAZ、 SEZ6L2、 CDIPT、 ASPHD1、 KCTD13、TMEM219、 TAOK2、 DOC2A、TBX6等;患儿父母染色体芯片检查结果均未发现异常。确诊为16p11.2缺失综合征。②检索国内外报道的关于16p11.2缺失相关病例共1 378例,临床表型涉及到神经系统表现547例（39.7%）,内分泌系统371例（26.9%）,生长发育与骨骼异常84例（6.1%）,泌尿生殖与消化系统10例（0.7%）,心血管系统4例（0.3%）,免疫功能异常1例（0.07%）,由于缺失片段大小不一,导致临床表型具有较大的异质性。结论 多发骨骼畸形（尤其脊柱侧弯）,伴神经系统异常（如癫痫、孤独症等）,其他系统累及（如反复感染、内分泌异常等）应考虑16p11.2缺失综合征可能,通过染色体芯片检测技术以及高密度寡核苷酸微阵列比较基因组杂交技术帮助诊断。     

Ellis–van Creveld syndrome associated with chronic intestinal pseudo‐obstruction

Ellis–van Creveld (EVC) syndrome is a rare autosomal recessive disorder characterized by hypoplastic nails, polydactyly, and achondroplasia. Patients usually exhibit normal cognitive function and no remarkable developmental delay. We herein present an unusual case of EVC syndrome. A Japanese 2‐year‐old boy was born at term, but immediately developed severe respiratory failure due to thorax deformity, postaxial polydactyly and nail hypoplasia. We identified a novel pattern of germinal compound heterozygous nonsense EVC2 mutations of c.1814C > A (p. S605X) and c.2653C > T (p. R885X), leading to the diagnosis of EVC syndrome. Interestingly, he also had severe developmental delay, and suddenly developed excessive abdominal distension at the age of 2. On surgery, extensive necrotic bowel with chronic intestinal pseudo‐obstruction was noted. This is, to our knowledge, a most severe phenotype of EVC syndrome, illustrating that the specific pattern of EVC2 compound heterozygous mutations may cause severe developmental delay and intestinal malfunction.     

Two children with obesity‐related glomerulopathy identified in a school urinary screening program

The incidence of obesity‐related glomerulopathy (ORG) has increased over the last decade, but there have been few reports on ORG in Japanese children. Reported herein are two children with ORG identified on school urinary screening (SUS). Patient 1 was a 12‐year‐old boy in whom proteinuria was first detected on SUS. His body mass index (BMI) was 33.8 kg/m² and he had hypertension and hyperuricemia. Patient 2, a 10‐year‐old boy, also had proteinuria identified on SUS. His BMI was 34.8 kg/m², and he had fatty liver, hyperuricemia, and hypercholesterolemia. Both were diagnosed with ORG based on obesity, proteinuria, and renal pathological findings. After treatment, including candesartan, food restriction and physical exercise, urinary protein excretion was decreased in both cases. We believe that such school urinary screening programs may be effective for the early identification and treatment of children with ORG.     

1p36 deletion syndrome associated with Prader–Willi‐like phenotype

Background: 1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes, characterized by moderate to severe mental retardation, characteristic facial appearance, hypotonia, obesity, and seizures. The clinical features often overlap with those of Prader–Willi syndrome (PWS). To elucidate the phenotype–genotype correlation in 1p36 deletion syndrome, two cases involving a PWS‐like phenotype were analyzed on molecular cytogenetics. Methods: Two patients presenting with the PWS‐like phenotype but having negative results for PWS underwent fluorescence in situ hybridization (FISH). The size of the chromosome 1p36 deletions was characterized using probes of BAC clones based on the University of California, Santa Cruz (UCSC) Genome Browser. Results: PWS was excluded on FISH and methylation‐specific polymerase chain reaction. Subsequent FISH using the probe D1Z2 showed deletion of the 1p36.3 region, confirming the diagnosis of 1p36 deletion syndrome. Further analysis characterized the 1p36 deletions as being located between 4.17 and 4.36 Mb in patient 1 and between 4.89 and 6.09 Mb in patient 2. Conclusion: Patients with 1p36 deletion syndrome exhibit a PWS‐like phenotype and are therefore probably underdiagnosed. The possible involvement of the terminal 4 Mb region of chromosome 1p36 in the PWS‐like phenotype is hypothesized.     

Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: Report of two cases and review of the literature

Basal cell nevus syndrome (BCNS; Gorlin syndrome) is an autosomal dominant disorder, characterized by a predisposition to neoplasms and developmental abnormalities. BCNS is caused by mutations in the human homolog of the Drosophila patched gene-1, PTCH1 , which is mapped on chromosome 9q22.3. Nonsense, frameshift, in-frame deletions, splice-site, and missense mutations have been found in the syndrome. Haploinsufficiency of PTCH1 , which is caused by interstitial deletion of 9q22.3, is also responsible for the syndrome. To date, 19 cases with interstitial deletion of long arm of chromosome 9 involving the region of q22 have been reported. We describe two unrelated patients with some typical features of BCNS associated with deletion of 9q21.33-q31.1 and determined the boundary of the deletion by fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) clones. The results showed that the size of deletions is between 15.33 and 16.04 Mb in patient 1 and between 18.08 and 18.54 Mb in patient 2. Although the size and breakpoints were different from those of previously reported cases, the clinical features are common to patients with 9q22 deletion associated with BCNS. Delineation of the 9q22 deletions and further consideration of the genes responsible for the characteristic manifestations may provide insight into this newly recognized deletion syndrome.     

Familial cases with MYH9 disorders caused by MYH9 S96L mutation

We report familial cases with MYH9 disorders: a 1‐year‐old Japanese boy who presented only with macrothrombocytopenia, and his 33‐year‐old father who had been diagnosed with refractory chronic idiopathic thrombocytopenic purpura, and suffered from hearing loss and chronic renal failure. Peripheral blood smears revealed giant platelets but no Döhle body‐like cytoplasmic inclusion bodies in neutrophils. Heterozygous MYH9 S96L mutations were found in the patient and his father, resulting in the diagnosis of a familial case with MYH9 disorders. The possibility of MYH9 disorders including Epstein syndrome should be assessed in cases of thrombocytopenia through the careful examination of hematological features.     

Hearing impairment in a female infant with interstitial deletion of 2q24.1q24.3

Patients with interstitial deletions in 2q24.1q24.3 are rarely reported. These patients manifest a variety of clinical features in addition to intellectual disability, depending on the size and location of the deletion. We report a female patient with interstitial deletion of 5.5 Mb in 2q24.1q24.3, who showed intrauterine growth retardation, hypotonia, global developmental delay, microcephaly, and characteristic facial appearance. In addition, she had hearing impairment, with no auditory brainstem response. Case of 2q24.1q24.3 deletion with hearing impairment is quite rare. We suspect that hearing impairment is caused by bilateral cochlear nerve deficiency due to cochlear nerve canal stenosis. Further studies are necessary to evaluate hearing impairment as a clinical feature in patients with de novo heterozygous 2q24.1q24.3 deletion.     

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).