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1.  12p13.33 microdeletion including ELKS/ERC1, a new locus associated with childhood apraxia of speech 
Speech sound disorders are heterogeneous conditions, and sporadic and familial cases have been described. However, monogenic inheritance explains only a small proportion of such disorders, in particular in cases with childhood apraxia of speech (CAS). Deletions of <5 Mb involving the 12p13.33 locus is one of the least commonly deleted subtelomeric regions. Only four patients have been reported with such a deletion diagnosed with fluorescence in situ hybridisation telomere analysis or array CGH. To further delineate this rare microdeletional syndrome, a French collaboration together with a search in the Decipher database allowed us to gather nine new patients with a 12p13.33 subtelomeric or interstitial rearrangement identified by array CGH. Speech delay was found in all patients, which could be defined as CAS when patients had been evaluated by a speech therapist (5/9 patients). Intellectual deficiency was found in 5/9 patients only, and often associated with psychiatric manifestations of various severity. Two such deletions were inherited from an apparently healthy parent, but reevaluation revealed abnormal speech production at least in childhood, suggesting variable expressivity. The ELKS/ERC1 gene, which encodes for a synaptic factor, is found in the smallest region of overlap. These results reinforce the hypothesis that deletions of the 12p13.33 locus may be responsible for variable phenotypes including CAS associated with neurobehavioural troubles and that the presence of CAS justifies a genetic work-up.
doi:10.1038/ejhg.2012.116
PMCID: PMC3522191  PMID: 22713806
array CGH; 12p13.33; inherited deletion; ELKS/ERC1 gene; speech delay; childhood apraxia of speech (CAS)
2.  Phenotypic and functional consequences of haploinsufficiency of genes from exocyst and retinoic acid pathway due to a recurrent microdeletion of 2p13.2 
Background
Rare, recurrent genomic imbalances facilitate the association of genotype with abnormalities at the “whole body” level. However, at the cellular level, the functional consequences of recurrent genomic abnormalities and how they can be linked to the phenotype are much less investigated.
Method and results
We report an example of a functional analysis of two genes from a new, overlapping microdeletion of 2p13.2 region (from 72,140,702-72,924,626). The subjects shared intellectual disability (ID), language delay, hyperactivity, facial asymmetry, ear malformations, and vertebral and/or craniofacial abnormalities. The overlapping region included two genes, EXOC6B and CYP26B1, which are involved in exocytosis/Notch signaling and retinoic acid (RA) metabolism, respectively, and are of critical importance for early morphogenesis, symmetry as well as craniofacial, skeleton and brain development. The abnormal function of EXOC6B was documented in patient lymphoblasts by its reduced expression and with perturbed expression of Notch signaling pathway genes HES1 and RBPJ, previously noted to be the consequence of EXOC6B dysfunction in animal and cell line models. Similarly, the function of CYP26B1 was affected by the deletion since the retinoic acid induced expression of this gene in patient lymphoblasts was significantly lower compared to controls (8% of controls).
Conclusion
Haploinsufficiency of CYP26B1 and EXOC6B genes involved in retinoic acid and exocyst/Notch signaling pathways, respectively, has not been reported previously in humans. The developmental anomalies and phenotypic features of our subjects are in keeping with the dysfunction of these genes, considering their known role. Documenting their dysfunction at the cellular level in patient cells enhanced our understanding of biological processes which contribute to the clinical phenotype.
doi:10.1186/1750-1172-8-100
PMCID: PMC3710273  PMID: 23837398
2p13 deletion; EXOC6B; CYP26B1; Developmental delay; Cranial/skeletal anomalies
3.  Genetic education for primary care providers 
Canadian Family Physician  2009;55(12):e92-e99.
ABSTRACT
OBJECTIVE
To increase primary care providers’ awareness and use of genetic services; increase their knowledge of genetic issues; increase their confidence in core genetic competencies; change their attitudes toward genetic testing for hereditary diseases; and increase their confidence as primary care genetic resources.
DESIGN
Participants completed a workshop and 3 questionnaires: a baseline questionnaire, a survey that provided immediate feedback on the workshop itself, and a follow-up questionnaire 6 months later.
SETTING
Ontario.
PARTICIPANTS
Primary care providers suggested by deans of nursing, midwifery, family medicine, and obstetric programs, as well as coordinators of nurse practitioner programs, in Ontario and by the Ontario College of Family Physicians.
INTERVENTION
A complex educational intervention was developed, including an interactive workshop and PowerPoint educational modules on genetic topics for participants’ use (available at www.mtsinai.on.ca/FamMedGen/).
MAIN OUTCOME MEASURES
Awareness and use of genetic services, knowledge of genetics, confidence in core clinical genetic skills, attitudes toward genetic testing, and teaching activities related to genetics.
RESULTS
The workshop was attended by 29 participants; of those, 21 completed the baseline questionnaire and the 6-month follow-up questionnaire. There was no significant change found in awareness or reported use of genetic services. There was significant improvement in self-assessed knowledge of (P = .001) and confidence in (P = .005) skills related to adult-onset genetic disorders. There were significant increases in confidence in many core genetic competencies, including assessing risk of hereditary disorders (P = .033), deciding who should be offered referral for genetic counseling (P = .003), discussing prenatal testing options (P = .034), discussing benefits, risks, and limitations of genetic testing (P = .033), and describing what to expect at a genetic counseling session (P = .022). There was a significant increase in the number of primary care providers agreeing that genetic testing was beneficial in the management of adult-onset diseases (P = .031) and in their confidence in being primary care genetic resources for adult-onset genetic disorders (P = .006).
CONCLUSION
Educational interventions that include interactive peer resource workshops and educational modules can increase knowledge of and confidence in the core competencies needed for the delivery of genetic services in primary care.
PMCID: PMC2793208  PMID: 20008584
4.  Submicroscopic deletions of 11q24-25 in individuals without Jacobsen syndrome: re-examination of the critical region by high-resolution array-CGH 
Background
Jacobsen syndrome is a rare contiguous gene disorder that results from a terminal deletion of the long arm of chromosome 11. It is typically characterized by intellectual disability, a variety of physical anomalies and a distinctive facial appearance. The 11q deletion has traditionally been identified by routine chromosome analysis. Array-based comparative genomic hybridization (array-CGH) has offered new opportunities to identify and refine chromosomal abnormalities in regions known to be associated with clinical syndromes.
Results
Using the 1 Mb BAC array (Spectral Genomics), we screened 70 chromosomally normal children with idiopathic intellectual disability (ID) and congenital abnormalities, and identified five cases with submicroscopic abnormalities believed to contribute to their phenotypes. Here, we provide detailed molecular cytogenetic descriptions and clinical presentation of two unrelated subjects with de novo submicroscopic deletions within chromosome bands 11q24-25. In subject 1 the chromosome rearrangement consisted of a 6.18 Mb deletion (from 128.25–134.43 Mb) and an adjacent 5.04 Mb duplication (from 123.15–128.19 Mb), while in subject 2, a 4.74 Mb interstitial deletion was found (from 124.29–129.03 Mb). Higher resolution array analysis (385 K Nimblegen) was used to refine all breakpoints. Deletions of the 11q24-25 region are known to be associated with Jacobsen syndrome (JBS: OMIM 147791). However, neither of the subjects had the typical features of JBS (trigonocephaly, platelet disorder, heart abnormalities). Both subjects had ID, dysmorphic features and additional phenotypic abnormalities: subject 1 had a kidney abnormality, bilateral preauricular pits, pectus excavatum, mild to moderate conductive hearing loss and behavioral concerns; subject 2 had macrocephaly, an abnormal MRI with delayed myelination, fifth finger shortening and squaring of all fingertips, and sensorineural hearing loss.
Conclusion
Two individuals with ID who did not have the typical clinical features of Jacobsen syndrome were found to have deletions within the JBS region at 11q24-25. Their rearrangements facilitate the refinement of the JBS critical region and suggest that a) deletion of at least 3 of the 4 platelet function critical genes (ETS-1, FLI-1 and NFRKB and JAM3) is necessary for thrombocytopenia; b) one of the critical regions for heart abnormalities (conotruncal heart defects) may lie within 129.03 – 130.6 Mb; c) deletions of KCNJ1 and ADAMTS15 may contribute to the renal anomalies in Jacobsen Syndrome; d) the critical region for MRI abnormalities involves a region from 124.6 – 129.03 Mb. Our results reiterate the benefits of array-CGH for description of new phenotype/genotype associations and refinement of previously established ones.
doi:10.1186/1755-8166-1-23
PMCID: PMC2648978  PMID: 19000322
5.  Metabolic Syndrome features and risk of neural tube defects 
Background
Maternal obesity and pre-pregnancy diabetes mellitus, features of the metabolic syndrome (MetSyn), are individual risk factors for neural tube defects (NTD). Whether they, in combination with additional features of MetSyn, alter this risk is not known. We evaluated the risk of NTD in association with maternal features of the MetSyn.
Methods
We used a population-based case-control study design in the province of Ontario, Canada. Cases and controls were derived from women who underwent antenatal maternal screening (MSS) at 15 to 20 weeks' gestation. There were 89 maternal cases with, and 434 controls without, an NTD-affected singleton pregnancy. Maternal features of MetSyn were defined by the presence of pre-pregnancy diabetes mellitus, body weight ≥ 90th centile among controls, non-white ethnicity and/or serum highly sensitive C-reactive protein (hsCRP) ≥ 75th centile of controls. Since hsCRP naturally increases in pregnancy, analyses were performed with, and without, the inclusion of hsCRP in the model.
Results
Mean hsCRP concentrations were exceptionally high among study cases and controls (6.1 and 6.4 mg/L, respectively). When hsCRP was excluded from the model, the adjusted odds ratios for NTD were 1.9 (95% confidence interval 1.1–3.4) in the presence 1 feature of MetSyn, and 6.1 (1.1–32.9) in the presence of 2 or more features. When hsCRP was included, the respective risk estimates were attenuated to 1.6 (0.88–2.8) and 3.1 (1.2–8.3).
Conclusion
We found about 2-fold and 6-fold higher risk for NTD in the presence 1, and 2 or more features, of the metabolic syndrome, respectively. It is not clear whether this risk is altered by the presence of a high serum hsCRP concentration.
doi:10.1186/1471-2393-7-21
PMCID: PMC2039731  PMID: 17880716

Results 1-5 (5)