SLDB

Speech/Language Disorders Database

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Gene / phenotype associations for SETBP1

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Entrez Id Symbol Location Disorder Brief Phenotype Reference Year Download
26040 SETBP1 18q21.1 Expressive language skills Filges et al 2011 JSON | XML

Additional Phenotype Details: May be assessed using the expressive language scale of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992).

Reference

Semel EM, Wiig EH, Secord W (1992) Clinical evaluation of language fundamentals—revised. Phychological Corporation, San Antonio.

Basic Study Type:  - aCGH (array comparative genomic hybridization) - FISH (fluorescence in situ hybridisation) - Genetic expression analysis - Candidate gene sequencing

Study Cohort: 
Summary:

- aCGH, FISH: Two male patients with developmental and expressive speech delay
(Genetic expression analysis for one of these and one normal control)

- Candidate gene sequencing: 142 patients with developmental delay and 70 normal controls (all Japanese)

Detail on the two patients:
"Patient 1 (DECIPHER #TWM253969) is a 7-year old boy, the second child of non-consanguineous parents (https://decipher.sanger.ac.uk/). His 10-year-old sister is healthy and normally developed. He was born with a birth weight of 2504 g (3-10th centile), length of 47 cm (10-25th centile), and occipitofrontal circumference (OFC) of 33.5 cm (=50th centile). At the time of his birth, his father and mother were 34 and 40 years old, respectively. His development was moderately delayed with crawling at 1 year, free walking at 2 years, and the first word at 5 years. He suffered febrile seizures several times, but EEG and brain MRI showed no abnormal findings. At 7 years, his height was 115 cm (25-50th centile), weight was 15.0 kg (<3rd centile), and OFC was 49.3 cm (3-10th centile). He showed distinctive facial features with an inverted triangle face, prominent forehead, ptosis with periorbital fullness, epicanthus and pointed chin (figure 1A). He can walk by himself and can speak only a few words. The Kyoto developmental scale measured his developmental quotient as 40, which indicated moderate developmental delay. Visual acuity examination showed a refractive error of +8D in both eyes, indicating hyperopia. Previously performed conventional chromosomal analysis showed a normal male karyotype of 46,XY.
"Patient 2, the 3rd child of non-consanguineous healthy parents, was born at 38 weeks by caesarean section for breech presentation after an uneventful pregnancy. In the neonatal period, the boy was hypotonic, sleepy and passive and rarely cried. He showed significantly delayed motor development, with sitting at 14 months and walking at 2 years, as well as delayed pincer grip. Initially, a discrete hemiparesis of the left part of his body manifested only while running with a slight spastic posture of his left hand and gait asymmetry suggested a perinatal or prenatal stroke. Cerebral MRI at the age of 4 years was normal except an unspecific T2 hyperintense infratentorial lesion in the right cranial paramedian cerebellum. The patient still exhibits coordination deficits in fine motoricity. His growth parameters are in the normal range (75th-90th centile), and OFC is within the 10th-25th centile. Hearing was found to be normal. Interestingly, the boy has not developed any expressive speech at all to date, whereas receptive language abilities are intact. He actively communicates using gestures illustrating his demands and ideas, but well understands his interlocutor, permitting a bidirectional exchange. He exhibits kind and social behaviour but at the same time a restless search for interactive communication. He has difficulty concentrating and has no sense of danger or pain. Facial dysmorphisms include frontal upsweep, a lighter blond hair corona in the front, hypertelorism, ptosis of eyelids predominantly on the left, periorbital fullness, straight and sparse eyebrows, flat nasal bridge, short nose, thin upper lip, short fingers and broad distal phalanges (figure 1B-D). No major malformations have been found. Microcytic hypochrome anaemia remains unexplained; the search for HbH inclusion bodies which would indicate X-linked alpha-thalassaemia/ mental retardation syndrome was negative."

Genotyping Methods: 
Microarray-based comparative genomic hybridisation (aCGH)

"aCGH analyses were performed using the Human Genome CGH Microarray 44K (Agilent Technologies, Santa Clara, California, USA) and the whole genome tiling NimbleGen CGH array (Human CGH 2.1M WG-T v2.0; NimbleGen; Roche NimbleGen Inc, Madison, Wisconsin, USA) for patient 1 and patient 2, respectively, according to the manufacturer’s protocols."

Fluorescence in situ hybridisation

"Identified aberrations were confirmed by fluorescence in situ hybridisation (FISH) using locus-specific BAC clones as probes. In patient 1, two clones, CTD-3236P11 on 18q12.3 (chr18:40 779 351-40 864 576) as a target and RP11-105C15 on 18p11.31 (chr18:5 910 725-60 63 460) as a marker, were selected from the UCSC genome browser (http://www.genome.ucsc.edu). In patient 2, the locus-specific probe RP11-24L5 (BlueGnome, Cambridge, UK) in the region 18q12.3 (chr18:40 588 784-40 776 858) was used on metaphase spreads. Physical positions refer to the March 2006 human reference sequence (NCBI Build 36.1)."

Cohort study of SETBP1

"A total of 142 Japanese patients with developmental delay, without genomic copy number aberrations as determined by aCGH, participated in the cohort study [4]. SETBP1 sequences were analysed by the standard PCR-direct sequencing method. The primers used for PCR and the big-dye sequencing reaction (Life Technologies) were designed using Primer3 (http://primer3.sourceforge.net/)
(supplemental online table 1). When we identified nucleotide changes in samples for which parental samples were available, trio analyses were performed to check whether the changes were de novo or familial. The nucleotide sequences of SETBP1, in which nucleotide alterations were found in the cohort study, were compared with homologues in species including Callithrix jacchus, Gorilla gorilla, Macaca mulatta, Pan troglodytes, Pongo pygmaeus, Tarsius syrichta and Tupaia belangeri,which were identified using Gene Tree (http://www.ensembl.org). DNA samples from 70 Japanese volunteers were used for the control cohort of normal Japanese."

Analysis Methods: 
- aCGH analysis, confirmed using FISH, to identify abberations in the two patients

- Comparison of SETBP1 expression in skin fibroblasts in one of the patients and one normal control

- Sequencing of SETBP1 in cohort study

Other Details: 
Expression analysis of SETBP1

"Total RNAs were extracted from cultured skin fibroblasts from patient 1 and the control individual using the ISOGEN RNA extraction kit (Wako, Osaka, Japan), reverse-transcribed to complementary DNA (cDNA) using the SuperScript VILO cDNA Synthesis Kit (Life Technologies, Carlsbad, California, USA) according to the manufacturer’s instructions, then used as templates for real-time PCR using Power SYBR Green PCR master mix (Life Technologies). Primers for SETBP1 mRNA were designed in the coding region (SETBP1 nt374F; 5'-GTCCA CCTGAGATCAAGATC-3' and SETBP1 nt663R; 5'-GTCCATGTGGTTCTGGCTGC-39). Beta actin primers (59-GGCACCCAGCACAATGAAGATC-3' and 5'-AAGTCATAGTCCGCCTAGAAGC-3') were used for the internal control. Real-time PCR amplifications were performed in three independent replicates on an ABI7500 (Life Technologies), and the data were evaluated by the Delta Delta Ct method [2]. The SETBP1 expression ratio (patient versus normal control) was calculated in each of the three examinations.
"Concentrations of SETBP1 in the cell lysates of skin fibroblasts from patient 1 and the control were also analysed by western blotting using the SETBP1 MaxPab mouse polyclonal antibody (B01), catalogue number H00026040-B01 (Abnova, Taipei City, Taiwan) as described previously [3]."


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26040 SETBP1 18q21.1 Expressive language impairment Marseglia et al 2012 JSON | XML

Additional Phenotype Details: May be assessed using the expressive language scale of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992).

Reference

Semel EM, Wiig EH, Secord W (1992) Clinical evaluation of language fundamentals—revised. Phychological Corporation, San Antonio.

Basic Study Type:  - Metaphase spread - aCGH analyses (array comparative genomic hybridization) - qRT-PCR (quantitative real-time polymerase chain reaction)

Study Cohort: 
Summary:

5-year old boy with severe language impairment, verbal dyspraxia

Detail:

"A 5 year old boy was referred to us for speech delay. The patient was the third child of healthy unrelated Caucasian parents with two healthy siblings. Family history revealed maternal grandmother with epilepsy and one maternal cousin with mental retardation. The patient was born after an uneventful term pregnancy. Delivery was normal and birth weight was 3650 g (0 DS), length was 49 cm (0 SDS), and head circumference was 35 cm (0 SD). There was no notion of muscular hypotonia, sucking reflex was valid. Growth parameters reached the 97th percentile during the first year of life. Psychomotor development milestones were slightly delayed with sitting at about 9 months and walking at the age of 18 months. His babbling was very poor during the first year. During preschool age the patient showed fine motor skills impairment (manual dyspraxia and global coordination difficulties). At 3 y he started to produce some sounds to communicate intentions, however nonverbal communication skills were very poor. He exhibits behavioural problems (hyperactivity and attention deficit) and overall autistic like features (no interest in peers play shared activities, repetitive and atypical interests in objects). From 4 year he started a program of AAC (Augmentative and Alternative Communication), learning to use of a book-album with images and photos to show questions, objects and actions. Afterward he showed a considerable communicative intentionality and improvements in social skills, despite he didn’t develop verbal skills. At 5 y the neuropsychological assessment showed severe language impairment with verbal dyspraxia (he said four ”words” mono and bi-syllabic) and better language’s comprehension skills.
"Psychometric testing (Leiter-R VR and AR battery), performed at the age of 10 years, showed mild mental retardation, IQ brief score was 58, Fluid Reasoning score was 52. He showed higher impairment of non-verbal memory and attention and better skills in associative memory. Difficulties emerged in “visual-spatial” tasks, in “visual-motor” organization and on the “graphic-representative” side. Language development was severely affected with significant differences between expressive and receptive language skills. At 13 y the T.R.O.G test (Test for Reception of Grammar) indicated that his lexical and grammatical comprehension skills were comparable to a child younger than 4. At 16 y speech is almost absent. He actively communicates with surprising effectiveness using gestures and mimic expression of face and body. He also presents remarkable narrative competence using a sequence of gestures to make sentences and displaying pictures and photos from his book-album to illustrates his requests and ideas. At physical examination we noted peculiar facial features (long face, high forehead, synophris, small palpebral fissures with ptosis, periorbital fullness, bilateral epicanthal folds, small nostrils, high nasal bridge, broad nasal tip, thin upper lip, fleshy lower tip, high-arched palate, small chin) and mild pectus excavatum (Fig. 1). Blood test and ECG were normal. Cardiac echo (14 y) and abdominal echo did not detect abnormalities. Cerebral RMI (6 y) was normal, except for a minimal alteration in signal of the peritrigonal white matter. Spectroscopy during RMI didn’t show creatinine deficit. Hearing and ABR (6 y) were within the normal limits (only asymmetric, with slowing of the signal on the left). EEG (6 y) showed poor organization of the background rhythm and diffuse slowing (no epileptiform potentials)."

Genotyping Methods: 
"Chromosome analysis was performed according to standard procedures on QFQ-banded metaphase spread from peripheral blood lymphocytes at 350/450-band level."

". . .an oligo array-CGH was performed using the Human Genome CGH 44K Microarray Kit (Agilent Technologies, Santa Clara, CA, USA), according to the manufacturer’s protocols. The Agilent Feature Extraction software has been used to perform image analysis. In order to correct systematic spatial and intensity biases, the results were normalized using the lowess function. Normalised log2 ratio values were calculated and breakpoint identification was performed applying the Shifting Level Model (SLM) segmentation algorithm [1]. The probabilistic classification of each segmented region into biologically motivated status (loss, neutral or gain) was performed by FastCall algorithm [2]."

"To confirm array-CGH data, qRT-PCR was performed both on patient and relatives, using TaqMan CopyNumber Assays on SETBP1, according to the manufacturer’s protocols (Applied Biosystems, http://products.appliedbiosystems.com). The data were analysed using CopyCaller Software (http://www.appliedbiosystems.com/support/software/copycaller/) and the results confirmed the presence of a de novo deletion in the patient."

Other Details: 
Chromosomal abberation

"Conventional chromosomal analysis showed the presence of an apparently balanced translocation [46XY, t(2; 18)(q24; q21)]. . .Despite the results of conventional cytogenetic, array-CGH analysis revealed an interstitial microdeletion of chromosome 18 of about 372 kb [arr 18q12.3(40,786,241-41,158,305)x1].


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