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Human chromosomal studies in Kuala Lumpur

Yip MY, Yong HS, Dhaliwal SS

Med J Malaysia, 1978 Jun;32(4):316-20.
PMID: 732631
Matched MeSH terms: Intellectual Disability/genetics
Bohring-opitz syndrome - A case of a rare genetic disorder

Visayaragawan N, Selvarajah N, Apparau H, Kamaru Ambu V

Med J Malaysia, 2017 08;72(4):248-249.
PMID: 28889139 MyJurnal

The diagnostic challenge of Bohring-Opitz Syndrome, a rare genetic disorder has haunted clinicians for ages. Our patient was born at term via caesarean-section with a birth weight of 1.95 kilograms. She had mild laryngomalacia, gastroesophageal reflux disease and seizures. Physical signs included microcephaly, hemangioma, low set ears, cleft palate, micrognatia and the typical BOS posture. Chromosomal analysis showed 46 xx -Bohring-Opitz Syndrome overlapped with C- syndrome. Goal-directed holistic care with integration of parent/carer training was started very early. She succumbed to a Respiratory- Syncitial-Virus and Pseudomonas pneumonia complicated with sepsis at the age of two years and 11 months.

Matched MeSH terms: Intellectual Disability/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: Intellectual Disability/genetics
Fulltext Prevalence of chromosomal anomalies of the mentally retarded--report of a study of 124 institutionalised children in Kuala Lumpur

Noor PJ, Chin YM, Ten SK, Hassan K

Singapore Med J, 1987 Jun;28(3):235-40.
PMID: 2958941

A cytogenetic survey 01 124 children in lour special schools for the mentally handicapped was carried out to determine the contribution of chromosomal abnormalities to the aetiology of mental retardation in these children. All the children were karyotyped employing the G·banding technique 01 43 (34.7%) with an abnormal chromosome complement, 40 had Down's Syndrome, and 3 had other chromosomal abnormalities, namely a translocation 1;17, a mosaic male/trisomy 18 and a Klinefelter's syndrome. Polymorphic variants involving chromosomes 1, 9, and 14 were also observed. Two other children showed variants of the Y chromosome (one a small Y and the other a metacentric Y). The possible contribution by these abnormal variants to mental retardation is discussed. Details of the abnormal cytogenetic findings are reported.

Matched MeSH terms: Intellectual Disability/genetics*
Expanding the phenotype of PPP1R21-related neurodevelopmental disorder

Almannai M, Marafi D, Zaki MS, Maroofian R, Efthymiou S, Saadi NW, et al.

Clin Genet, 2024 Jun;105(6):620-629.
PMID: 38356149 DOI: 10.1111/cge.14492

PPP1R21 encodes for a conserved protein that is involved in endosomal maturation. Biallelic pathogenic variants in PPP1R21 have been associated with a syndromic neurodevelopmental disorder from studying 13 affected individuals. In this report, we present 11 additional individuals from nine unrelated families and their clinical, radiological, and molecular findings. We identified eight different variants in PPP1R21, of which six were novel variants. Global developmental delay and hypotonia are neurological features that were observed in all individuals. There is also a similar pattern of dysmorphic features with coarse faces as a gestalt observed in several individuals. Common findings in 75% of individuals with available brain imaging include delays in myelination, wavy outline of the bodies of the lateral ventricles, and slight prominence of the bodies of the lateral ventricles. PPP1R21-related neurodevelopmental disorder is associated with a consistent phenotype and should be considered in highly consanguineous individuals presenting with developmental delay/intellectual disability along with coarse facial features.

Matched MeSH terms: Intellectual Disability/genetics
Novel biallelic SZT2 mutations in 3 cases of early-onset epileptic encephalopathy

Tsuchida N, Nakashima M, Miyauchi A, Yoshitomi S, Kimizu T, Ganesan V, et al.

Clin Genet, 2018 02;93(2):266-274.
PMID: 28556953 DOI: 10.1111/cge.13061

The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.

Matched MeSH terms: Intellectual Disability/genetics*
Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients

Sekiguchi F, Tsurusaki Y, Okamoto N, Teik KW, Mizuno S, Suzumura H, et al.

J Hum Genet, 2019 Dec;64(12):1173-1186.
PMID: 31530938 DOI: 10.1038/s10038-019-0667-4

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.

Matched MeSH terms: Intellectual Disability/genetics*
Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures

Nakashima M, Tohyama J, Nakagawa E, Watanabe Y, Siew CG, Kwong CS, et al.

J Hum Genet, 2019 Apr;64(4):313-322.
PMID: 30655572 DOI: 10.1038/s10038-018-0559-z

Casein kinase 2 (CK2) is a serine threonine kinase ubiquitously expressed in eukaryotic cells and involved in various cellular processes. In recent studies, de novo variants in CSNK2A1 and CSNK2B, which encode the subunits of CK2, have been identified in individuals with intellectual disability syndrome. In this study, we describe four patients with neurodevelopmental disorders possessing de novo variants in CSNK2A1 or CSNK2B. Using whole-exome sequencing, we detected two de novo variants in CSNK2A1 in two unrelated Japanese patients, a novel variant c.571C>T, p.(Arg191*) and a recurrent variant c.593A>G, p.(Lys198Arg), and two novel de novo variants in CSNK2B in Japanese and Malaysian patients, c.494A>G, p.(His165Arg) and c.533_534insGT, p.(Pro179Tyrfs*49), respectively. All four patients showed mild to profound intellectual disabilities, developmental delays, and various types of seizures. This and previous studies have found a total of 20 CSNK2A1 variants in 28 individuals with syndromic intellectual disability. The hotspot variant c.593A>G, p.(Lys198Arg) was found in eight of 28 patients. Meanwhile, only five CSNK2B variants were identified in five individuals with neurodevelopmental disorders. We reviewed the previous literature to verify the phenotypic spectrum of CSNK2A1- and CSNK2B-related syndromes.

Matched MeSH terms: Intellectual Disability/genetics
Identification of chromosome 21 materials using the whole chromosome 21 specific library

Isa MN, Boyd E, Turner TL, Tolmie J, Connor JM

Southeast Asian J Trop Med Public Health, 1995;26 Suppl 1:92-5.
PMID: 8629150

The chromosome in situ suppression hybridization or chromosome painting technic was applied to confirm and eliminate the markers involving chromosome 21 segments using a chromosome 21 DNA library. The library ATCCLL21SNO2 was amplified, directly biotinylated using the polymerase chain reaction. The results demonstrated a translocation of chromosome 21 material on chromosome 2 and X and eliminate the origin of the marker. Thus, the technique provides an important tool to complement the conventional G-banding technic.

Matched MeSH terms: Intellectual Disability/genetics*
Fulltext Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel

Brett M, McPherson J, Zang ZJ, Lai A, Tan ES, Ng I, et al.

PLoS One, 2014;9(4):e93409.
PMID: 24690944 DOI: 10.1371/journal.pone.0093409

Developmental delay and/or intellectual disability (DD/ID) affects 1-3% of all children. At least half of these are thought to have a genetic etiology. Recent studies have shown that massively parallel sequencing (MPS) using a targeted gene panel is particularly suited for diagnostic testing for genetically heterogeneous conditions. We report on our experiences with using massively parallel sequencing of a targeted gene panel of 355 genes for investigating the genetic etiology of eight patients with a wide range of phenotypes including DD/ID, congenital anomalies and/or autism spectrum disorder. Targeted sequence enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq2000 using paired-end reads. For all eight patients, 81-84% of the targeted regions achieved read depths of at least 20×, with average read depths overlapping targets ranging from 322× to 798×. Causative variants were successfully identified in two of the eight patients: a nonsense mutation in the ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third patient, a canonical splice site variant in the USP9X gene could likely explain all or some of her clinical phenotypes. These results confirm the value of targeted MPS for investigating DD/ID in children for diagnostic purposes. However, targeted gene MPS was less likely to provide a genetic diagnosis for children whose phenotype includes autism.

Matched MeSH terms: Intellectual Disability/genetics*
Fulltext Familial complex chromosomal rearrangement in a dysmorphic child with global developmental delay

Ngim CF, Keng WT, Ariffin R

Singapore Med J, 2011 Oct;52(10):e206-9.
PMID: 22009409

We report the unusual case of a dysmorphic child with global developmental delay secondary to a familial complex chromosomal rearrangement (CCR). His chromosomal analysis using G-banding and dual colour fluorescence in situ hybridisation with whole chromosome paint revealed a supernumerary marker chromosome as a result of malsegregation of a familial CCR involving chromosomes 7, 12 and 14. The balanced form of this familial CCR was also carried by the patient's mother and maternal grandmother, both of whom had a history of recurrent spontaneous abortions, as well as his maternal uncle, who was infertile. To the best of our knowledge, this is the first reported case of familial CCR involving chromosomes 7, 12 and 14. This case also highlights the importance of chromosomal analysis in children with dysmorphism and developmental delay as well as in adults who suffer from recurrent spontaneous abortions or infertility.

Matched MeSH terms: Intellectual Disability/genetics*
Fulltext Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases

Maas RR, Iwanicka-Pronicka K, Kalkan Ucar S, Alhaddad B, AlSayed M, Al-Owain MA, et al.

Ann Neurol, 2017 Dec;82(6):1004-1015.
PMID: 29205472 DOI: 10.1002/ana.25110

OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1.
METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported.
RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills.
INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.

Matched MeSH terms: Intellectual Disability/genetics*
Fulltext Cornelia de Lange syndrome in diverse populations

Dowsett L, Porras AR, Kruszka P, Davis B, Hu T, Honey E, et al.

Am J Med Genet A, 2019 02;179(2):150-158.
PMID: 30614194 DOI: 10.1002/ajmg.a.61033

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

Matched MeSH terms: Intellectual Disability/genetics*

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