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Fulltext Novel population specific autosomal copy number variation and its functional analysis amongst Negritos from Peninsular Malaysia

Mokhtar SS, Marshall CR, Phipps ME, Thiruvahindrapuram B, Lionel AC, Scherer SW, et al.

PLoS One, 2014;9(6):e100371.
PMID: 24956385 DOI: 10.1371/journal.pone.0100371

Copy number variation (CNV) has been recognized as a major contributor to human genome diversity. It plays an important role in determining phenotypes and has been associated with a number of common and complex diseases. However CNV data from diverse populations is still limited. Here we report the first investigation of CNV in the indigenous populations from Peninsular Malaysia. We genotyped 34 Negrito genomes from Peninsular Malaysia using the Affymetrix SNP 6.0 microarray and identified 48 putative novel CNVs, consisting of 24 gains and 24 losses, of which 5 were identified in at least 2 unrelated samples. These CNVs appear unique to the Negrito population and were absent in the DGV, HapMap3 and Singapore Genome Variation Project (SGVP) datasets. Analysis of gene ontology revealed that genes within these CNVs were enriched in the immune system (GO:0002376), response to stimulus mechanisms (GO:0050896), the metabolic pathways (GO:0001852), as well as regulation of transcription (GO:0006355). Copy number gains in CNV regions (CNVRs) enriched with genes were significantly higher than the losses (P value <0.001). In view of the small population size, relative isolation and semi-nomadic lifestyles of this community, we speculate that these CNVs may be attributed to recent local adaptation of Negritos from Peninsular Malaysia.

Matched MeSH terms: Chromosome Disorders/genetics*
De novo ring chromosome 6 in a child with multiple congenital anomalies

Ahzad HA, Ramli SF, Loong TM, Salahshourifar I, Zilfalil BA, Yusoff NM

Kobe J Med Sci, 2010;56(2):E79-84.
PMID: 21063149

Ring chromosome 6, especially if it is de novo, is a rare occurrence. The phenotype of patients with ring chromosome 6 can be highly variable ranging from almost normal to severe malformations and mental retardation. The size and structure of the ring chromosome as well as the level of mosaicism are important factors in determining the clinical phenotype. Here we report an eight month-old child, a product of a non consanguineous marriage, who presented with developmental retardation, hypertelorism, microcephaly, flat occiput, broad nasal bridge, large ears, micrognathia, wide spaced nipples, protruding umbilicus, short stubby fingers, clinodactyly, single palmar crease, short neck with no obvious webbing, and congenital heart defect. Conventional karyotyping and Whole Chromosome Paint of the peripheral leukocytes showed 46,XY,r(6)(p25q27) karyotype with plausible breakpoints at p25 and q27 end. Conventional karyotyping of both parents showed normal karyotype. To the best of our knowledge, this is the first report of a Malay individual with ring chromosome 6, and this report adds to the collective knowledge of this rare chromosome abnormality.

Matched MeSH terms: Chromosome Disorders/genetics
Fulltext Chromosomal abnormalities and reproductive outcome in Malaysian couples with miscarriages

Pal S, Ma SO, Norhasimah M, Suhaida MA, Siti Mariam I, Ankathil R, et al.

Singapore Med J, 2009 Oct;50(10):1008-12.
PMID: 19907893

This study was done to determine the prevalence of chromosomal abnormalities and the subsequent reproductive outcome in couples who had two or more miscarriages.

Matched MeSH terms: Chromosome Disorders/genetics
Fulltext Interstitial deletion of the distal long arm of chromosome 4, del (4)(q33-q35), in association with paternal balanced translocation

Mdzin R, Ko C, Abdul Latif Z, Zakaria Z

Singapore Med J, 2008 Nov;49(11):e336-9.
PMID: 19037546

Interstitial deletions of the long arm of chromosome 4 are rare. The deletions may occur at the proximal or the distal portions of the chromosome and different breakpoints may be involved. We report an interstitial deletion of 4q: 46XY der 4 (q28;q35) in a six-year-old boy with dysmorphic features associated with moderate mental retardation. Parental chromosomal analysis showed a balanced paternal translocation.

Matched MeSH terms: Chromosome Disorders/genetics
Fulltext A rare case of ambiguous genitalia

Ng SF, Boo NY, Wu LL, Shuib S

Singapore Med J, 2007 Sep;48(9):858-61.
PMID: 17728969

Genes on the Y chromosome are essential for normal sex determination and sex differentiation of male genitalia. However, genes on the X chromosome and other autosomes have been shown to be anti-testes and have a detrimental effect on this process. Addition of X chromosomes to the 46,XY karyotype results in seminiferous tubules dysgenesis, hypogonadism and malformed genitalia. We report a term male newborn with 49,XXXXY syndrome presenting with ambiguous genitalia, multiple extra-gonadal anomalies, facial dysmorphism, and radioulnar synostosis.

Matched MeSH terms: Sex Chromosome Disorders/genetics*
Duplication 17p11.2 (Potocki-Lupski Syndrome) in a child with developmental delay

Shuib S, Saaid NN, Zakaria Z, Ismail J, Abdul Latiff Z

Malays J Pathol, 2017 Apr;39(1):77-81.
PMID: 28413209 MyJurnal

Potocki-Lupski syndrome (PTLS), also known as duplication 17p11.2 syndrome, trisomy 17p11.2 or dup(17)(p11.2p11.2) syndrome, is a developmental disorder and a rare contiguous gene syndrome affecting 1 in 20,000 live births. Among the key features of such patients are autism spectrum disorder, learning disabilities, developmental delay, attention-deficit disorder, infantile hypotonia and cardiovascular abnormalities. Previous studies using microarray identified variations in the size and extent of the duplicated region of chromosome 17p11.2. However, there are a few genes which are considered as candidates for PTLS which include RAI1, SREBF1, DRG2, LLGL1, SHMT1 and ZFP179. In this report, we investigated a case of a 3-year-old girl who has developmental delay. Her chromosome analysis showed a normal karyotype (46,XX). Analysis using array CGH (4X44 K, Agilent USA) identified an ~4.2 Mb de novo duplication in chromosome 17p11.2. The result was confirmed by fluorescence in situ hybridization (FISH) using probes in the critical PTLS region. This report demonstrates the importance of microarray and FISH in the diagnosis of PTLS.

Matched MeSH terms: Chromosome Disorders/genetics
Early transition from insulin to sulfonylureas in neonatal diabetes and follow-up: Experience from China

Li X, Xu A, Sheng H, Ting TH, Mao X, Huang X, et al.

Pediatr Diabetes, 2018 03;19(2):251-258.
PMID: 28791793 DOI: 10.1111/pedi.12560

BACKGROUND: Sulfonylurea therapy can improve glycemic control and ameliorate neurodevelopmental outcomes in patients suffering from neonatal diabetes mellitus (NDM) with KCNJ11 or ABCC8 mutations. As genetic testing results are often delayed, it remains controversial whether sulfonylurea treatment should be attempted immediately at diagnosis or doctors should await genetic confirmation.
OBJECTIVE: This study aimed to investigate the effectiveness and safety of sulfonylurea therapy in Chinese NDM patients during infancy before genetic testing results were available.
METHODS: The medical records of NDM patients with their follow-up details were reviewed and molecular genetic analysis was performed. Sulfonylurea transfer regimens were applied in patients diagnosed after May 2010, and glycemic status and side effects were evaluated in each patient.
RESULTS: There were 23 NDM patients from 22 unrelated families, 10 had KCNJ11 mutations, 3 harbored ABCC8 mutations, 1 had INS mutations, 4 had chromosome 6q24 abnormalities, 1 had a deletion at chromosome 1p36.23p36.12, and 4 had no genetic abnormality identified. Sixteen NDM infants were treated with glyburide at an average age of 49 days (range 14-120 days) before genetic confirmation. A total of 11 of 16 (69%) were able to successfully switch to glyburide with a more stable glucose profile. The responsive glyburide dose was 0.51 ± 0.16 mg/kg/d (0.3-0.8 mg/kg/d), while the maintenance dose was 0.30 ± 0.07 mg/kg/d (0.2-0.4 mg/kg/d). No serious adverse events were reported.
CONCLUSIONS: Molecular genetic diagnosis is recommended in all patients with NDM. However, if genetic testing results are delayed, sulfonylurea therapy should be considered before such results are received, even in infants with newly diagnosed NDM.

Matched MeSH terms: Chromosome Disorders/genetics