The Manitoba Youth Justice Program: empowering and supporting youth with FASD in conflict with the law.

Fetal alcohol spectrum disorder (FASD) describes a constellation of physical, cognitive, neurologic, and behavioral impairments resulting from prenatal exposure to alcohol. FASD is recognized as being one of the most common causes of preventable brain injury in children. There had long been concerns that some youth in conflict with the law may be affected with FASD given repetitive patterns of offending and apparent lack of understanding of the consequences of their actions. In 2004, funding was received from Justice Canada for a pilot project with a cross-departmental steering committee working together to determine a best way of working across systems to provide FASD assessments to these youth. It was recognized that provision of timely FASD assessments would allow the court to provide more meaningful sentences taking into account the youth's strengths and challenges and enhance the changes of decreased recidivism and increased changes of rehabilitation. This paper describes the basic science around FASD and its diagnosis, provides a history of the FASD Youth Justice Program, and reports on legal issues, structure, statistics, accomplishments, and ongoing future challenges.

Intragenic loss of function mutations demonstrate the primary role of FMR1 in fragile X syndrome.

Nearly all cases of fragile X syndrome result from expansion of a CGG trinucleotide repeat found in the 5' untranslated portion of the FMR1 gene. Methylation of the expanded repeats correlates with down-regulation of transcription of FMR1; thus fragile X syndrome is postulated to be due to a loss of function of the FMR1 gene product, and this has been demonstrated at the protein level. However, the nature of the mutation offers the possibility of methylation spreading to adjacent genes with consequent loss of expression and contribution to the phenotype. Deletions of FMR1 and flanking sequence (some of substantial size) have been reported in patients with phenotypes consistent with a diagnosis of fragile X-syndrome, however, none is strictly intragenic. We report here the identification of two different intragenic loss of function mutations in FMR1: a single de novo nucleotide deletion in a young male patient (IJ) and an inherited two basepair change in an Adult male (SD), each with classical features of fragile X syndrome.

Genetic implications and health consequences following the Chernobyl nuclear accident.

It has been almost 25 years since the Chernobyl nuclear accident in Ukraine. We review relevant data derived from published reports originating in the Former Soviet Union. We cite census data from Ukraine and research studies from Western Europe that analyzed the effect of radiation on genetics and health outcome in the exposed populations. We also present philatelic materials that pictorially captured that fateful event in history.

A founder mutation in BBS2 is responsible for Bardet-Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders.

Bardet-Biedl syndrome (BBS) is a multisystem genetically heterogeneous disorder, the clinical features of which are largely the consequence of ciliary dysfunction. BBS is typically inherited in an autosomal recessive fashion, and mutations in at least 14 genes have been identified. Here, we report the identification of a founder mutation in the BBS2 gene as the cause for the increased incidence of this developmental disorder in the Hutterite population. To ascertain the Hutterite BBS locus, we performed a genome-wide single nucleotide polymorphism (SNP) analysis on a single patient and his three unaffected siblings from a Hutterite family. The analysis identified two large SNP blocks that were homozygous in the patient but not in his unaffected siblings, one of these regions contained the BBS2 gene. Sequence analysis and subsequent RNA studies identified and confirmed a novel splice site mutation, c.472-2A>G, in BBS2. This mutation was also found in homozygous form in three subsequently studied Hutterite BBS patients from two different leuts, confirming that this is a founder mutation in the Hutterite population. Further studies are required to determine the frequency of this mutation and its role, if any, in the expression of other ciliopathies in this population.

Face-brain asymmetry in autism spectrum disorders.

The heterogeneity of autism spectrum disorders (ASDs) confounds attempts to identify causes and pathogenesis. Identifiable endophenotypes and reliable biomarkers within ASDs would help to focus molecular research and uncover genetic causes and developmental mechanisms. We used dense surface-modelling techniques to compare the facial morphology of 72 boys with ASD and 128 first-degree relatives to that of 254 unrelated controls. Pattern-matching algorithms were able to discriminate between the faces of ASD boys and those of matched controls (AUC=0.82) and also discriminate between the faces of unaffected mothers of ASD children and matched female controls (AUC=0.76). We detected significant facial asymmetry in boys with ASD (P<0.01), notably depth-wise in the supra- and periorbital regions anterior to the frontal pole of the right hemisphere of the brain. Unaffected mothers of children with ASD display similar significant facial asymmetry, more exaggerated than that in matched controls (P<0.03) and, in particular, show vertical asymmetry of the periorbital region. Unaffected fathers of children with ASD did not show facial asymmetry to a significant degree compared to controls. Two thirds of unaffected male siblings tested were classified unseen as more facially similar to unrelated boys with ASD than to unrelated controls. These unaffected male siblings and two small groups of girls with ASD and female siblings, all show overall directional asymmetry, but without achieving statistical significance in two-tailed t-tests of individual asymmetry of ASD family and matched control groups. We conclude that previously identified right dominant asymmetry of the frontal poles of boys with ASD could explain their facial asymmetry through the direct effect of brain growth. The atypical facial asymmetry of unaffected mothers of children with ASD requires further brain studies before the same explanation can be proposed. An alternative explanation, not mutually exclusive, is a simultaneous and parallel action on face and brain growth by genetic factors. Both possibilities suggest the need for coordinated face and brain studies on ASD probands and their first-degree relatives, especially on unaffected mothers, given that their unusual facial asymmetry suggests an ASD susceptibility arising from maternal genes.

Molecular cytogenetic investigation of two patients with Y chromosome rearrangements and intellectual disability.

We describe two males with intellectual disability (ID) and facial dysmorphism, both of whom have non-mosaic Y chromosome rearrangements resulting in deletions of large portions of the Y chromosome. Patient A, with ID, mild dysmorphism, speech delay, Duane anomaly of the eye, hypermetropia and conductive hearing loss, had two structurally rearranged Y chromosomes resulting in both p and q arm deletions in addition to a Yp duplication. Patient B, also with speech and language delay, developmental delay and short stature, had an interstitial deletion of Yq11.21-11.23. Array-CGH excluded the presence of additional submicroscopic rearrangements at the 1 Mb resolution level. A review of males with Y chromosome rearrangements and ID was performed. Our study provides a more detailed molecular cytogenetic assessment of Y rearrangements in individuals with ID than has been previously possible, and facilitates assessment and comparison of other individuals with a Y chromosome rearrangement.

Reduced affinity of the androgen receptor for 5 alpha-dihydrotestosterone but not methyltrienolone in a form of partial androgen resistance. Studies on cultured genital skin fibroblasts.

We have studied a child with posterior labial fusion, clitoral phallus, female urethra, and a short, blind vagina born to a mother with decreased axillary and pubic hair. Her karyotype is 46,XY. At 2 yr of age, the child's basal level of plasma testosterone was less than 0.35 nM and after human chorionic gonadotropin stimulation, it rose to 2.6. Testis and epididymis histology were normal. Her cultured genital (labial) skin fibroblasts have normal testosterone 5 alpha-reductase activity, and metabolize 5 alpha-dihydrotestosterone (DHT) normally, but they do not augment (up-regulate) their basal androgen-receptor binding activity during prolonged incubation with DHT. With DHT, the androgen receptor in her genital skin fibroblasts has a normal binding capacity (maximum binding capacity = 25 fmol/mg protein), but an increased rate constant of dissociation (k = 11.6 X 10(-3) min-1; normal, 6 +/- 1.2 (+/- SD)), and a decreased apparent equilibrium binding affinity (Kd = 0.6 nM; normal, 0.22 +/- 0.09) that is evident in the results of 2-h assays but not of those lasting 0.5 h. With the synthetic androgen, methyltrienolone, all three binding properties of the receptor are normal, and her receptor activity up-regulates normally. We interpret these results to mean that the subject has a ligand-selective defect in the time-dependent transformation of initial, low-affinity androgen-receptor complexes to serial states of higher affinity, presumably as the result of a structural mutation at the X-linked locus that encodes the androgen receptor protein.

Floating-Harbor syndrome and celiac disease.

We report on a 17-year-old young woman with a speech impediment, developmental delay, short stature, and facial anomalies consistent with the Floating-Harbor syndrome (FHS). In addition, she has clinical and histological evidence of celiac disease, which was observed in 1 of the 6 previously reported cases of FHS, suggesting a possible association between the 2 conditions or pleiotropism of a presumed autosomal recessive disorder.

Male-to-male transmission of mild Brachmann-de Lange syndrome.

We report on a father and son with mild Brachmann-de Lange syndrome. Previous reports have documented apparent autosomal dominant transmission; however, only one example of male-to-male transmission of possible Brachmann-de Lange syndrome has been reported. This case provides further evidence of the existence of an autosomal dominant form of Brachmann-de Lange syndrome.

Tibial agenesis, femoral duplication, and caudal midline anomalies.

Tibial agenesis with femoral duplication (Gollop-Wolfgang complex) and cloacal exstrophy are each rare malformations. Thus, their concurrence in an individual is an extremely rare event. We report on a patient born with distal duplication of the right femur, agenesis of the right tibia and hallux, cloacal exstrophy, and sacral defects. Review of the small group of cases reported with femoral duplication and tibial agenesis in association with caudal midline defects demonstrated a pattern of anomalies that while varying in presentation and severity was quite specific. We postulate that this disorder is related to misexpression of one or more distal HOX genes, potentially HOX10 or HOX11, leading to abnormal induction and proliferation of caudal mesenchyme.

Ulnar agenesis and endocardial fibroelastosis.

We report on an infant with bilateral ulnar agenesis, radial hypoplasia, oligodactyly, hydrops fetalis, and endocardial fibroelastosis (EFE). The presence of the 2 major malformations and parental consanguinity suggests the possibility of a new autosomal recessive MCA syndrome.

Segregation analysis of rare autosomal folate sensitive fragile sites.

We have studied 12 families with rare autosomal folate sensitive fragile sites (RAFSFS). Of these, 9 were informative for segregation analysis of fragile sites in order to assess differences in parental transmission. We identified 20 families with RAFSFS from the literature from 1985 to 1989; thirteen of these were informative for segregation analysis. Segregation analysis confirmed that paternal fragile site transmission rates deviated significantly from the expected 50% for a Mendelian co-dominant trait. Sex ratio comparisons showed a significant excess of transmitting females and a significant excess of males among fragile site non-carriers from the literature families. Comparison of the fragile site carriers with non-carriers in the combined data showed a non-significant excess of non-carriers. We confirmed a deficiency of offspring expressing fragile sites when transmission was through fathers, suggesting gametic selection or the phenomenon of parental genomic imprinting.

Bilateral sensorineural deafness and hydrocephalus due to foramen of Monro obstruction in sibs: a newly described autosomal recessive disorder.

We identified a Canadian-Mennonite family in which a brother and sister have hydrocephalus due to obstruction at the foramen of Monro and profound bilateral sensorineural deafness. This appears to be a unique combination of anomalies and, to our knowledge, has not been reported previously. Both parents and a brother are phenotypically normal. The parents are second cousins. Thus, on the basis of consanguinity, affected sibs of both sexes, and in the absence of evidence for intrauterine infections or other adverse perinatal events, this syndrome is likely inherited in an autosomal recessive fashion.

Familial transmission of a small supernumerary marker chromosome 8 identified by FISH: an update.

A father and his 2 daughters were previously determined to carry a small, supernumerary marker chromosome [Chudley et al., 1983]. The origin of this marker could not be determined by standard cytogenetic techniques. In this study, fluorescence in situ hybridization (FISH) studies identified the marker chromosome as a pericentric derivative of chromosome 8. The father has low grade mosaicism for this marker and is phenotypically normal. Both daughters are non-mosaic and show developmental delays and somewhat differing clinical findings. The phenotypes of the 2 sisters are compared with those previously reported for supernumerary der(8) patients. This is the first report of familial transmission of a supernumerary der(8) marker chromosome.

Recognizable behavioral and somatic phenotype in patients with proximal interstitial 18q deletion: report on a new affected child and follow-up on the original reported familial cases.

We describe a moderately retarded boy with a chromosome 18 deletion involving the regions q11.2q12.2. His phenotype is similar to that of other reported cases of proximal interstitial deletions involving 18q. We also provide follow-up information on the first 4 cases of proximal interstitial deletion of 18q from a family with a complex chromosome rearrangement originally reported in 1974.

Short-term memory and cognitive variability in adult fragile X females.

We investigated the possibility that adult fragile X [fra(X)] heterozygotes have a distinct or specific cognitive profile, with a particular focus on visuospatial and/or memory deficits. With a sample of 13 adult fra(X) female carriers (2 fra(X) positive) and age-matched control women, we performed 2 tests: Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Revised Visual Retention Test (RVRT). An identifiable cognitive profile was not evident in the study group, but significant differences were evident in RVRT performance in number correct and number of errors when compared to controls and normative data. The combination of the WAIS-R and RVRT data suggests that the short-term memory component of the tasks may be of more significance than visuospatial performance in the deficits observed.

Proximal interstitial 6q deletion: a recognizable syndrome.

We report on an 8-year-old boy with a proximal interstitial deletion of the long arm of chromosome 6 with breakpoints q13 to q14.2. He has a characteristic facial appearance that is seen in several of the previously described cases. Details of his clinical course are reviewed and compared with the nine previous reported cases of the proximal deletion 6q syndrome.

Mosaic trisomy of a small r(1) with an abnormal phenotype.

Cytogenetic studies of a mildly dysmorphic 10-year-old male with mild developmental delay and learning difficulties revealed mosaicism for a supernumerary ring chromosome in approximately half of the cells. The karyotype of this patient was established as 47,XY,+r[15]/46,XY[15].ish r(1)(D1Z7+,wcp1-). Although the presence of euchromatic material was shown by C banding, the lack of hybridization with the whole chromosome paint 1 (wcp1) probe suggests that few unique sequences are contained in the ring and that these sequences likely explain the child's dysmorphic features and developmental delay. A review of the literature, including the present case, suggests that the significance of euchromatin in supernumerary r(1) as determined by both C banding and fluorescence in situ hybridization (FISH) with chromosome 1 painting probes can be used as a prognostic indicator for potential severity of the clinical phenotype.

Vertical transmission of the Ohdo blepharophimosis syndrome.

Ohdo blepharophimosis syndrome (OBS) is a multiple congenital anomalies-mental retardation syndrome composed of blepharophimosis, ptosis, dental hypoplasia, partial deafness, and mental retardation. Previously reported cases of OBS have been sporadic except for the report by Ohdo et al. [1986, J Med Genet 23:242-244] that described two affected sisters and a first cousin favoring autosomal recessive inheritance. The original report by Ohdo et al. [1986] may reflect nonpenetrance of an autosomal dominantly inherited disorder or genetic heterogeneity of OBS. We report on a child and the mother who have blepharophimosis, ptosis, dental anomalies, mild hearing loss, and mental retardation. Chromosome analysis in both showed a balanced paracentric inversion of the long arm of chromosome 9, which was also present in two phenotypically normal sibs of the mother. This is the first report of vertical transmission of OBS suggestive of autosomal dominant inheritance. X-linked dominant and mitochondrial inheritance are other possible modes of inheritance.