Increased Diagnostic Yield of Array Comparative Genomic Hybridization for Autism Spectrum Disorder in One Institution in Taiwan.

Background and Objectives: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNVs) and is recommended for the initial genetic testing of patients with autism spectrum disorder (ASD). This study aims to determine the diagnostic yield of array comparative genomic hybridization (array-CGH) in ASD patients from a cohort of Chinese patients in Taiwan. Materials and Methods: Enrolled in this study were 80 ASD children (49 males and 31 females; 2-16 years old) followed up at Taipei MacKay Memorial Hospital between January 2010 and December 2020. The genomic DNA extracted from blood samples was analyzed by array-CGH via the Affymetrix GeneChip Genome-Wide Human single nucleotide polymorphism (SNP) and NimbleGen International Standards for Cytogenomic Arrays (ISCA) Plus Cytogenetic Arrays. The CNVs were classified into five groups: pathogenic (pathologic variant), likely pathogenic (potential pathologic variant), likely benign (potential normal genomic variant), benign (normal genomic variant), and uncertain clinical significance (variance of uncertain significance), according to the American College of Medical Genetics (ACMG) guidelines. Results: We identified 47 CNVs, 31 of which in 27 patients were clinically significant. The overall diagnostic yield was 33.8%. The most frequently clinically significant CNV was 15q11.2 deletion, which was present in 4 (5.0%) patients. Conclusions: In this study, a satisfactory diagnostic yield of array-CGH was demonstrated in a Taiwanese ASD patient cohort, supporting the clinical usefulness of array-CGH as the first-line testing of ASD in Taiwan.

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

BACKGROUND: 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. METHODS: 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. CONCLUSIONS: 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.

Functional independence of Taiwanese children with Down syndrome.

AIM: Information regarding the functional strengths and weaknesses of children with Down syndrome is important for early intervention programmes and for agencies providing family support and educational services. METHOD: This study used the Functional Independence Measure for Children (WeeFIM) questionnaire for the parents or caregivers of 166 Taiwanese children (101 males and 65 females; median age 12y 7mo; range 3y 2mo-19y 1mo) with Down syndrome to assess their functional skills. RESULTS: Out of a potential score of 126, the mean total WeeFIM score was 101.2. There was no statistically significant difference between the scores from the male and female participants (100.4 [SD 21.4] vs 102.4 [SD 24.7]; p>0.05). The mean scores for three domains (self-care, mobility, and cognition) were 45, 33, and 23 respectively (maximum of 56, 35, and 35 respectively). Performance was strongest in the mobility domain and weakest in the cognition domain. The total WeeFIM scores and 18 subscores for the three domains all positively correlated with age (p<0.05). INTERPRETATION: For children with Down syndrome, some support and supervision is required for cognition and self-care tasks. The WeeFIM questionnaire may be useful for identifying the strengths and limitations of children with developmental disabilities and their families.

Clinical characteristics and survival of trisomy 13 in a medical center in Taiwan, 1985-2004.

BACKGROUND: This study investigated the survival and natural history of trisomy 13 in a series of patients, comparing the management and outcome before and after the implementation of Taiwan's National Health Insurance program (NHI). METHODS: A total of 28 cases of trisomy 13 seen at Mackay Memorial Hospital, Taipei, Taiwan, from 1985 to 2004 were retrospectively reviewed. Survival and management before (12 cases) and after (16 cases) the implementation of National Health Insurance were compared, and structural defects, imaging findings, and cytogenetic results were analyzed. The cases that were diagnosed prenatally, and finally terminated, were excluded from this study. The diagnosis of trisomy 13 was based on the postnatal chromosome analysis. RESULTS: All patients except one with trisomy 13 translocation died in their first year because of severe malformations of the cardiovascular or central nervous system. The median survival was 9 days. After implementation of National Health Insurance, survival with trisomy 13 was significantly longer than before (P < 0.05). The three most common structural defects were abnormal auricular helices or low-set ears (89%), cryptorchidism and abnormal scrotum of male (73%) and cleft lip and/or palate (71%). Using echocardiography, the most commonly detected heart defects were patent ductus arteriosus (68%), ventricular septal defect (50%) and atrial septal defect (50%), and eight cases (36%) had complex congenital heart defects. The most common brain lesion was lenticulostriate vasculopathy (22%), followed by holoprosencephaly (17%), brain edema (13%) and subependymal cyst (13%). CONCLUSIONS: Early diagnosis and the survival patterns from the data collected should be used to inform parents and health-care professionals to assist in decision making. Although most patients with trisomy 13 die within the first weeks after birth, it is important to recognize that a few may survive the first year. When counseling families, the long-term survival prospects of trisomy 13 patients should be included.

Cri-du-chat syndrome.

BACKGROUND: Cri-du-chat syndrome is a genetic disorder associated with various sized deletions of the short arm of chromosome 5. There are typical physical features, but individual phenotypes vary considerably. METHODS: The records of 23 patients with cri-du-chat syndrome admitted to Mackay Memorial Hospital from June 1984 to February 2006 were retrospectively reviewed. Data abstracted from the records included abnormal facial features and physical findings, results of echocardiography, bronchoscopy, auditory evoked potential, visual evoked potential, brain ultrasonography, and karyotype. We examined the various clinical phenotypes to see if there was an association with specific karyotypes. RESULTS: Among congenital heart conditions, atrial septal defect (8/15, 53%) was the most common, followed by ventricular septal defect (4/15, 26%), tricuspid regurgitation (4/15, 26%) and patent ductus arteriosus (3/15, 20%). Laryngomalacia was the most frequent airway problem (8/23, 34%) and strabismus the commonest visual disorder (1/23). A high percentage of patients had impaired hearing (5/23, 21%). There was no clear relationship found between deletion size and major clinical manifestations in this study. CONCLUSIONS: Karyotype is not a reliable indicator of specific organ involvement in cri-du-chat syndrome. However, karyotyping is still useful, particularly if parental translocation are found to be involved. It helps for prenatal diagnosis of next pregnancy.

Clinical characteristics and survival of trisomy 18 in a medical center in Taipei, 1988-2004.

Trisomy 18 is the second most common autosomal trisomy in newborns. The birth prevalence of this disorder is approximately 1 in 3,000 to 1 in 8,000, and the life span of the majority of patients is less than 1 year. As information regarding outcome in trisomy 18 is rather fragmentary in the literature, this study is aimed at investigating the survival and natural history of trisomy 18. We also evaluated the survival age and management of trisomy 18 in two different periods, before and after the implementation of National Health Insurance (NHI) program. Thirty-nine cases of trisomy 18 were collected in Mackay Memorial Hospital in a 17-year period, from 1988 to 2004. Delivery data, survival age, management before and after the implementation of NHI program, structural defects, image findings and cytogenetic results were analyzed by medical and nurse's records. The diagnosis of trisomy 18 was based on the prenatal amniocentesis or postnatal chromosome analysis. Three patients had trisomy 18 mosaicism. Since cardiovascular and central nervous systems are the most common organ systems involved in this disorder, 31 patients received brain ultrasonography and heart ultrasonography for evaluation of their multiple anomalies after admission. All patients except one died in their first year due to severe malformations of the cardiovascular or central nervous systems. The median survival age was 6 days. We found a longer survival with female patients than with male patients (P < 0.05). Implementation of NHI program in the more recent decade of this study period was associated with longer survival of trisomy 18 (P < 0.05). The three most common structural defects were clenched hands (95%), rocker bottom feet (90%), and low set or malformed ears (90%). Low birth weight was present in 90%. By cardiac ultrasonography, the top four heart defects were ventricular septal defect (94%), patent ductus arteriosus (77%) and atrial septal defect (68%). However, ten cases (32%) had complex congenital heart defects. By brain ultrasonography, the most common brain lesion was cerebellar hypoplasia (32%), followed by brain edema (29%), enlarged cisterna magna (26%) and choroid plexus cysts (19%). Although most patients with trisomy 18 die within the first few weeks after birth, it is important to recognize that a small but notable percentage of these patients will survive the first year. When prenatal or postnatal decisions need to be made, the possibility of long-term survival should be included in any discussion to enable families to make the most appropriate decision.