Array-CGH increased the diagnostic rate of developmental delay or intellectual disability in Taiwan.

Unexplained developmental delay or intellectual disability (DD/ID) has an estimated prevalence of about 3%-5% in the general population of Taiwan. Array comparative genomic hybridization (array-CGH) is a high-resolution tool that can detect about 50 Kb chromosome aberrations. A previous study has reported a detection rate of 10%-20% for this array.1 This study aimed to investigate and compare the diagnosis rate for DD/ID using array-CGH and conventional chromosome study in DD/ID patients in Taiwan. We enrolled 177 patients with DD/ID who underwent array-CGH examination at the MacKay Memory Hospital between June 2010 and September 2017. The copy number variants (CNV) were classified into the following three groups: pathogenic (potential pathologic variant), benign (normal genomic variant), and uncertain clinical significance (variance of uncertain significance, VOUS), according to the ACMG guideline.2 RESULTS: Of the 177 enrolled patients, 100 (56.5%) were men and 77 (43.5%) were women. Ages ranged from 3 months to 50 years, with a median age of 5.2 years. Total 32.0% (32/100) male patients had pathogenic CNV, and 32.5% (25/77) female patients had pathogenic CNV. The ratio of pathogenic CNV in male and female patients was not significantly different (p = 0.379). The proportions of pathogenic CNV at <3 years, 3-6 years, 6-12 years, 12-18 years, and >18 years of age were 32.3% (31/96), 19.4% (6/31), 34.8% (8/23), 16.7% (2/12), and 66.7% (10/15), respectively. The overall diagnosed rate of DD/ID with pathogenic CNV was 27.7% (49/177) using array-CGH in this study. There were 105 patients with conventional karyotyping and array-CGH data at the same time. Nineteen (18.1%) patients had visible chromosomal abnormality. Total 32/105 (30.5%) patients could find at least one pathogenic CNVs. The array-CGH had a higher diagnosed rate than the conventional karyotyping in clinical application. Although array-CGH could not detect point mutation, balanced translocations, inversions, or low-level mosaicism, the diagnosis rate in clinical application was up to 46.3% and 2.5 times that of conventional karyotyping analysis (18.1%). This study demonstrated that array-CGH is a powerful diagnostic tool and should be the first genetic test instead of conventional karyotyping analysis for patients with unexplained DD/ID.

Lee CL ，Lee CH ，Chuang CK ，Chiu HC ，Chen YJ ，Chou CL ，Wu PS ，Chen CP ，Lin HY ，Lin SP ... -  《-》

The clinical benefit of array-based comparative genomic hybridization for detection of copy number variants in Czech children with intellectual disability and developmental delay.

Wayhelova M ，Smetana J ，Vallova V ，Hladilkova E ，Filkova H ，Hanakova M ，Vilemova M ，Nikolova P ，Gromesova B ，Gaillyova R ，Kuglik P ... -  《BMC Medical Genomics》

Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes.

Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). Identification of genomic disorders in DD/ID. We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.

Di Gregorio E ，Riberi E ，Belligni EF ，Biamino E ，Spielmann M ，Ala U ，Calcia A ，Bagnasco I ，Carli D ，Gai G ，Giordano M ，Guala A ，Keller R ，Mandrile G ，Arduino C ，Maffè A ，Naretto VG ，Sirchia F ，Sorasio L ，Ungari S ，Zonta A ，Zacchetti G ，Talarico F ，Pappi P ，Cavalieri S ，Giorgio E ，Mancini C ，Ferrero M ，Brussino A ，Savin E ，Gandione M ，Pelle A ，Giachino DF ，De Marchi M ，Restagno G ，Provero P ，Cirillo Silengo M ，Grosso E ，Buxbaum JD ，Pasini B ，De Rubeis S ，Brusco A ，Ferrero GB ... -  《-》

Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?

Array comparative genomic hybridization (array CGH) is now widely adopted as a first-tier clinical diagnostic test in individuals with unexplained developmental delay/intellectual disability (DD/ID) and congenital anomalies. Our study aimed at enlarging the phenotypic spectrum associated with clinically relevant copy number variants (CNVs) as well as delineating clinical criteria, which may help separating patients with pathogenic CNVs from those without pathogenic CNVs. We performed a retrospective review of clinical and array CGH data of 342 children with unexplained DD/ID. The phenotypic features of patients with clinically significant CNV were compared with those without pathogenic CNVs. Array CGH detected pathogenic CNVs in 13.2% of the patients. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature and failure to thrive were clearly more frequent in children with pathogenic CNVs compared with children with normal array CGH results. Thus, we assume that in patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any of these features is part of the patient's phenotype.

Shoukier M ，Klein N ，Auber B ，Wickert J ，Schröder J ，Zoll B ，Burfeind P ，Bartels I ，Alsat EA ，Lingen M ，Grzmil P ，Schulze S ，Keyser J ，Weise D ，Borchers M ，Hobbiebrunken E ，Röbl M ，Gärtner J ，Brockmann K ，Zirn B ... -  《-》

[Molecular diagnosis of children with unexplained intellectual disability/ developmental delay by array-CGH].

He XY ，Chen XC ，Li R ，Li P ，Lu AM ... -  《-》