Chromosomal Microarray Analysis as a First-Tier Clinical Diagnostic Test in Patients With Developmental Delay/Intellectual Disability, Autism Spectrum Disorders, and Multiple Congenital Anomalies: A Prospective Multicenter Study in Korea

BACKGROUND: To validate the clinical application of chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic test and to determine the impact of CMA results on patient clinical management, we conducted a multicenter prospective study in Korean patients diagnosed as having developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA). METHODS: We performed both CMA and G-banding cytogenetics as the first-tier tests in 617 patients. To determine whether the CMA results directly influenced treatment recommendations, the referring clinicians were asked to complete a 39-item questionnaire for each patient separately after receiving the CMA results. RESULTS: A total of 122 patients (19.8%) had abnormal CMA results, with either pathogenic variants (N=65) or variants of possible significance (VPS, N=57). Thirty-five well-known diseases were detected: 16p11.2 microdeletion syndrome was the most common, followed by Prader-Willi syndrome, 15q11-q13 duplication, Down syndrome, and Duchenne muscular dystrophy. Variants of unknown significance (VUS) were discovered in 51 patients (8.3%). VUS of genes putatively associated with developmental disorders were found in five patients: IMMP2L deletion, PTCH1 duplication, and ATRNL1 deletion. CMA results influenced clinical management, such as imaging studies, specialist referral, and laboratory testing in 71.4% of patients overall, and in 86.0%, 83.3%, 75.0%, and 67.3% of patients with VPS, pathogenic variants, VUS, and benign variants, respectively. CONCLUSIONS: Clinical application of CMA as a first-tier test improves diagnostic yields and the quality of clinical management in patients with DD/ID, ASD, and MCA.

Multiple congenital anomalies-hypotonia-seizures syndrome 1: case report and review of literature / 中华儿科杂志

Objective@#To analyze and summarize the clinical and molecular characteristics of the patients with multiple congenital anomalies- hypotonia-seizures syndrome 1 (MCAHS 1).@*Method@#Clinical data and test results were collected from a patient who was diagnosed with confirmed genetic basis of MCAHS 1 in Shanghai Children′s Medical Center since December 2015. The patient and his parents were examined by the next generation sequencing (NGS) technology using peripheral blood genomic DNA, and the relevant mutations identified by NGS were verified with Sanger sequencing. Related literature was searched from PubMed and Embase databases (from their establishment to January 2017) by using "PIGN gene" as a keyword, the retrieved articles were further reviewed for the clinical manifestations, results and prognosis of PIGN related variants.@*Result@#A nearly 4-month-old Chinese boy was presented with epilepsy, hypotonia, developmental delay, accompanied by nearly normal laboratory test results. The NGS analysis revealed a compound heterozygous variations in the PIGN gene, included a known splice site mutation (c.963G>A) which was inherited from his father, and a novel nonsense mutation (c.2773A>T, p.Lys925*) which was inherited from his mother. Nine associated articles were retrieved. Including our patient, a total of 22 cases were identified as the PIGN variants. The most common clinical manifestations were developmental delay, hypotonia, and epilepsy.Missense varients were most frequently found. Prognosis was poor. Eight cases died, while survived cased suffered from refractory epilepsy, profound mental retardation, muscle weakness, etc.@*Conclusion@#MCAHS1 is characterized by epilepsy, severe developmental delay, hypotonia, and may be accompanied by multiple malformations of other systems. Homozygous or compound heterozygous variants in PIGN gene are the cause of the disease.

Chromosomal Microarray Testing in 42 Korean Patients with Unexplained Developmental Delay, Intellectual Disability, Autism Spectrum Disorders, and Multiple Congenital Anomalies

Chromosomal microarray (CMA) is a high-resolution, high-throughput method of identifying submicroscopic genomic copy number variations (CNVs). CMA has been established as the first-line diagnostic test for individuals with developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), and multiple congenital anomalies (MCAs). CMA analysis was performed in 42 Korean patients who had been diagnosed with unexplained DD, ID, ASDs, and MCAs. Clinically relevant CNVs were discovered in 28 patients. Variants of unknown significance were detected in 13 patients. The diagnostic yield was high (66.7%). CMA is a superior diagnostic tool compared with conventional karyotyping and fluorescent in situ hybridization.

A Case of Ring Chromosome 21 with Multiple Congenital Anomalies

Ring chromosome 21 causes a multitude of phenotypes, ranging from severe abnormalities to normal. The proposed mechanism of ring formation, breakage of both short and long arms of a chromosome with subsequent end to end fusion, remains unproven. We encountered a 4-year-old boy who presented developmental delay, microcephaly, micrognathia, hypertelorism, low-set ears, mild optic nerve hypoplasia, cleft lip and palate, scoliosis and left foot valgus, but normal brain MRI. Chromosome study from peripheral blood showed 46,XY, r(21)(p11.2q22.1) karyotype. The authors report the first case of ring chromosome 21 in Korea with a review of the literature.

A Case of Partial Trisomy 9 by Balanced Maternal Translocation

Trisomy 9p syndrome was first described by Rethore et al in 1970 and about 100 cases have been reported since. The phenotypic spectrum of this syndrome is characterized by craniofacial malformation, facial deformity, skeletal and dermatoglyphic anomalies with variable degrees of mental retardation. We experienced a case of partial trisomy 9 syndrome in a 15-month-old female who had multiple congenital anomalies of frontal bossing, oblique antimongoloid palpebral fissures, enophthalmos, hypertelorism, globular prominent nose, down-turned mouth, prominent low-set ears, simian creases of both hands, clinodactyly and single crease of 5th finger, congenital dislocation of both knees and mental retardation. In cytogenetic studies using G banding technique and fluorescent in situ hybridization(FISH), she presented with an extra derivative chromosome No. 9. The karyotype of the patient was confirmed as 47,XX,+der (9),t (6:9) (q27;q21.2) mat. We report the case with the review of the associated literatures.

A Case of 2q+ Syndrome Identified by Fluorescent In Situ Hybridization

We experienced a case of 2q+ syndrome in a neonate who had multiple congenital anomalies of long philtrum, a bow-shaped mouth, long fingers, and its second and fifth fingers overlapped with the third and the fourth. In the cytogenetic studies using G banding technique, an extra band of the distal long arm of chromosome 2 was shown. Because its extra chromosomal segment was too small and the parents' chromosome were normal, it was difficult to determine the origin of the additional segment. We could find the fluorescent signal from the extra chromosomal segment by using painting probe of chromosome 2. The karyotype of the patient was confirmed as 46, XX, 2q+. We reported the case with the review of the associated literatures.

A Case of 2q+ Syndrome Identified by Fluorescent In Situ Hybridization

We experienced a case of 2q+ syndrome in a neonate who had multiple congenital anomalies of long philtrum, a bow-shaped mouth, long fingers, and its second and fifth fingers overlapped with the third and the fourth. In the cytogenetic studies using G banding technique, an extra band of the distal long arm of chromosome 2 was shown. Because its extra chromosomal segment was too small and the parents' chromosome were normal, it was difficult to determine the origin of the additional segment. We could find the fluorescent signal from the extra chromosomal segment by using painting probe of chromosome 2. The karyotype of the patient was confirmed as 46, XX, 2q+. We reported the case with the review of the associated literatures.

A Case of Trisomy 9 Syndrome

Since Feingold and his collegues first described the trisomy 9 syndrome in 1973, approximately 30 patients with trisomy of the chromsome 9 have been described. Trisomy 9 has been reported as either partial or complete. Complete trisomy is rare and incompatible with a long life. Before this report, this syndrome has not been reported in Korea. A neonate was diagnosed trisomy 9 syndrome by clinical feature and chromosomal study. He had multiple anomalies such as broad-based nose, partially cleft lip, ambiguous genitalia, hyperconvex nails, overriding of fingers, and ventricular septal defect. The patient died at home on the 113th day of life.

A Case of Dup (3q) Syndrome

We have experienced a case of dup (3q) syndrome in the neonate who had a multiple congenital anomalies of hypertrichosis, hypertelorism, upslanting palpaberal fissures, anteverted nostrils, long philtrum, micrognathia, downturned corners of the mouth, highly arched palate, short, webbed neck, clinodactyly, rocker-bottom feet, dermal sinus. Cytogenetic studies showed a duplication 3q21-->qter regions. Chromosome study of relatives is extremely important for counseling because only 25% of cases represented de novo duplications. We reported the case with the review of the associated literatures.

A Case of 3p Partial Trisomy

3p partial trisomy is a rare chromosomal anomaly. We experienced a case of 3p partial trisomy in a male neonate. It was diagnosed by clinical and chromosoaml study. He had multiple anomalies such as brachycephaly, wide open fontanelle, square face, hypertelorism, mongoloid palpebral fissure, micrognathia, low set malformed ear, bilateral cleft lip and palate, double outlet right ventricle, atrial septal defect, ventricular septal defect, left ventricular hypoplasia, renal microcysts and micropenis. He was manifested intrauterine growth retardation. Peripheral blood chromosome studies showed an additional chromosomal material at the distal part of the short arm of chromosome 7. Analysis of chromosomes of family members showed that the father had normal karyotype, but the mother had reciprocal balanced translocation,46, XX, t(3;7)(p25;p22). The karyotype formula of the propositus was thus,46,XY,der(7),t(3;7)(p25;p22)mat, that is unbalanced for a duplication 3p25-->3pter, resulting from segregation of a balanced maternal translocation. Two years after patient's birth, his sister was born at 40 weeks of gestation without congenital anomalies. In the case of his sister, amniocentesis and chromosome studies had been done at 16 weeks of gestation. The result of the chromosome analysis was 46,XX,t(3;7)(p25;p22), as in her mother. We report a neonate with multiple congenital anomalies due to partial trisomy for the short arm of chromosome 3, his mother and a female sibling with t(3;7)(p25-->p22).

An unusual combination of trisomy 21 and partial trisomy 5q

The authors describe a male newborn with multiple congenital anomalies; craniofacial dysmorphism, bilateral cleft palate and lip, ambiguous external genitalia with absence of phallus, ventricular septal defect, agenesis of olfactory bulbs, and presence of small round cells simulating migration defect in the cerebellar white matter. Cytogenetic study demonstrated a chromosomal constitution of 47,XY, +21, +5q. Its pathological significance compared with Down's syndrome and hitherto reported partial trisomy 5q is discussed.