18q Deletion Syndrome Presenting with Late-Onset Combined Immunodeficiency.

Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4+ and/or CD8+ cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence.

Effects of Copy Number Variations on Developmental Aspects of Children With Delayed Development

OBJECTIVE: To determine effects of copy number variations (CNV) on developmental aspects of children suspected of having delayed development. METHODS: A retrospective chart review was done for 65 children who underwent array-comparative genomic hybridization after visiting physical medicine & rehabilitation department of outpatient clinic with delayed development as chief complaints. Children were evaluated with Denver Developmental Screening Test II (DDST-II), Sequenced Language Scale for Infants (SELSI), or Preschool Receptive-Expressive Language Scale (PRES). A Mann-Whitney U test was conducted to determine statistical differences of developmental quotient (DQ), receptive language quotient (RLQ), and expressive language quotient (ELQ) between children with CNV (CNV(+) group, n=16) and children without CNV (CNV(–) group, n=37). RESULTS: Of these subjects, the average age was 35.1 months (mean age, 35.1±24.2 months). Sixteen (30.2%) patients had copy number variations. In the CNV(+) group, 14 children underwent DDST-II. In the CNV(–) group, 29 children underwent DDST-II. Among variables, gross motor scale was significantly (p=0.038) lower in the CNV(+) group compared with the CNV(–) group. In the CNV(+) group, 5 children underwent either SELSI or PRES. In the CNV(–) group, 27 children underwent above language assessment examination. Both RLQ and ELQ were similar between the two groups. CONCLUSION: The gross motor domain in DQ was significantly lower in children with CNV compared to that in children without CNV. This result suggests that additional genetic factors contribute to this variability. Active detection of genomic imbalance could play a vital role when prominent gross motor delay is presented in children with delayed development.

Identification of ATP7B gene variant by combined use of Sanger sequencing, array CGH and quantitative PCR / 中华医学遗传学杂志

Objective@#To identify the type and origin of ATP7B gene mutation in a family affected with Wilson disease by combined use of multiple methods.@*Methods@#Peripheral blood samples were collected from the proband, her parents and her brother. Sanger sequencing were used to detect point mutation and small deletion/insertion of the 21 exons and flanking sequences of the ATP7B gene in all family members. Array-based comparative genomic hybridization (aCGH) was performed to identify copy number variations (CNVs) of the ATP7B gene in the proband. The result was validated by quantitative PCR (qPCR) in other 3 members.@*Results@#Sanger sequencing indicated that the proband carried a heterozygous variation c. 2668G>A (p.V890M) derived from her mother. In addition, 5 common SNPs were detected in her mother, three of which were also identified in her father and brother. The 5 SNPs in the proband were of the wide type. aCGH analysis demonstrated that the proband was heterozygous for a 4 kb deletion, which encompassed exons 2 and 3 of the ATP7B gene and 2 SNPs. qPCR showed that the copy number in her father and brother was about half of the control, indicating heterozygous loss of exons 2 and 3.@*Conclusion@#The combined Sanger sequencing, array CGH and qPCR has identified a novel CNV involving the ATP7B gene. The strategy can improve the diagnostic rate for hereditary or rare diseases.

2q37 Deletion syndrome confirmed by high-resolution cytogenetic analysis

Chromosome 2q37 deletion syndrome is a rare chromosomal disorder characterized by mild to moderate developmental delay, brachydactyly of the third to fifth digits or toes, short stature, obesity, hypotonia, a characteristic facial appearance, and autism spectrum disorder. Here, we report on a patient with 2q37 deletion presenting with dilated cardiomyopathy (DCMP). Congenital heart malformations have been noted in up to 20% of patients with 2q37 deletions. However, DCMP has not been reported in 2q37 deletion patients previously. The patient exhibited the characteristic facial appearance (a flat nasal bridge, deep-set eyes, arched eyebrows, and a thin upper lip), developmental delay, mild mental retardation, peripheral nerve palsy, and Albright hereditary osteodystrophy (AHO)-like phenotypes (short stature and brachydactyly). Conventional chromosomal analysis results were normal; however, microarray-based comparative genomic hybridization revealed terminal deletion at 2q37.1q37.3. In addition, the patient was confirmed to have partial growth hormone (GH) deficiency and had shown a significant increase in growth rate after substitutive GH therapy. Chromosome 2q37 deletion syndrome should be considered in the differential diagnosis of patients presenting with AHO features, especially in the presence of facial dysmorphism. When patients are suspected of having a 2q37 deletion, high-resolution cytogenetic analysis is recommended.

Small supernumerary marker chromosome and chromosome 18p abnormalities / 中华实用儿科临床杂志

Humans typically have 22 pairs of autosomal chromosomes in cells,and a pair of sex chromosomes.Some individuals have an extra,autosomal chromosome called a small supernumerary marker chromosome (sSMC).sSMC is a structurally abnormal chromosome fragment.The fragments are too small and no-specific banding pattern to be identified by conventional banding cytogenetic analysis.Array-based comparative genomic hybridization (aCGH),fluorescence in situ hybridization (FISH) or other molecular biological methods are necessary for the diagnosis.This article summarized the karyotype,pathogenesis,and the clinical manifestations of the sSMC-related chromosome 18p abnormalities.The patients with sSMC usually presented with abnormal chromosome syndrome.Some syndromes are relative common,such as Pallister-Killian syndrome,isochromosome 18p syndrome,Cat eye syndromes or Emanuel syndrome.sSMC is considered to be the frequent cause of mental retardation.The patients have no specific symptoms.With the progress of molecular cytogenetics,more sSMC has been identified.Genetic counseling and prenatal diagnosis are important to prevent sSMC.Molecular cytogenetic techniques are necessary to the diagnosis.

Diagnosis of one case with 7p15.3p22.1 microdeletion by applying array-based comparative genomic hybridization / 临床儿科杂志

Objective To investigate the diagnosis of a case with 7p15.3p22.1 microdeletion by applying array-based comparative genomic hybridization (array-CGH) and to analyze the relationship between the clinical manifestations and 7p15.3p22.1 microdeletion. Method Array-CGH technique was used to detect genomic copy number variations (CNVs) in an infant with normal karyotype after conventional chromosomal karyotyping. Results Array-CGH detected 7p15.3p22.1 deletion (chr7: 6777262-23981753), which was confirmed as pathogenic CNV after comparative analysis with database. Conclusion Array-CGH could serve as a useful complement for G-banding to be used in the clinical cytogenetic diagnosis.

Detection and analysis of genomic copy number variations in a 46,X0, +der(?) fetus by array-based comparative genomic hybridization / 基础医学与临床

Objective To understand genomic copy number variations (CNVs) and ascertain karyotype for a 46,X0, + der(?) fetus, and investigate possibility and superiority of array-based comparative genomic hybridization (array-CGH ) in clinical cytogenetic diagnosis. Methods G-banded chromosome analysis was carried out. The whole genome of the fetus was scanned and analysed by array-CGH. The results of array-CGH were confirmed by RT-qPCR. Results G-banded chromosome analysis showed that the fetal karyotype was 46,X0, +der(?). Array-CGH revealed the derivative chromosome as Y chromosome without CNVs. A total number of 118 submicroscopic CNVs were identified. Comparable results between array-CGH and RT-qPCR were obtained for 9 novel CNVs. Conclusion Comparing with conventional cytogenetic analysis, array-CGH is of high resolution, high-throughput and high accuracy, which provides a technical platform for accurate detection of submicroscopic chromosomal aberrations.