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One of our primary goals is to help families who have a child with an 18q deletion anticipate medical issues in order to optimize their child’s medical care. To this end we have narrowed the critical regions for four phenotypic features and determined the penetrance for each of those phenotypes when the critical region for that feature is hemizygous. We completed molecular analysis using oligo-array CGH and clinical assessments on 151 individuals with deletions of 18q and made genotype–phenotype correlations defining or narrowing critical regions. These nested regions, all within 18q22.3 to q23, were for kidney malformations, dysmyelination of the brain, growth hormone stimulation response failure, and aural atresia. The region for dysmyelination and growth hormone stimulation response failure were identical and was narrowed to 1.62 Mb, a region containing five known genes. The region for aural atresia was 2.3 Mb and includes an additional three genes. The region for kidney malformations was 3.21 Mb and includes an additional four genes. Penetrance rates were calculated by comparing the number of individuals hemizygous for a critical region with the phenotype to those without the phenotype. The kidney malformations region was 25% penetrant, the dysmyelination region was 100% penetrant, the growth hormone stimulant response failure region was 90% penetrant with variable expressivity, and the aural atresia region was 78% penetrant. Identification of these critical regions suggest possible candidate genes, while penetrance calculations begin to create a predictive phenotypic description based on genotype.

Most deletions of the long arm of chromosome 18 involve some part of the most distal 30 Mb. We have identified five individuals with cytogenetically diagnosed interstitial deletions that are all proximal to this commonly deleted region. The extent of their deletions was characterized using molecular and molecular cytogenetic techniques. Each participant was assessed under the comprehensive clinical evaluation protocol of the Chromosome 18 Clinical Research Center. Three of the five individuals were found to have apparently identical interstitial deletions between positions of 37.5 and 42.5 Mb (18q12.3 18q21.1). One individual's deletion was much larger and extended from a more proximal breakpoint position of 23 Mb (18q11.2) to a more distal breakpoint at 43 Mb (18q21.1). The fifth individual had a proximal breakpoint identical to the other three, but a distal breakpoint at 43.5 Mb (18q21.1). The clinical findings were of interest because the three individuals with the smaller deletions lacked major anomalies. All five individuals were developmentally delayed; however, the discrepancy between their expressive and receptive language abilities was striking, with expressive language being much more severely affected. This leads us to hypothesize that there are genes in this region of chromosome 18 that are specific to the neural and motor planning domains necessary for speech. Additionally, this may represent a previously underappreciated syndrome since these children do not have the typical clinical abnormalities that would lead to a chromosome analysis. © 2007 Wiley-Liss, Inc.

We report on a 12-year-old boy who presented with delayed development and CNS dysmyelination. Genetic studies showed a normal 46,XY karyotype by routine cytogenetic analysis, and 46,XY.ish del(18)(q23)(D18Z1+, MBP−) by FISH using a locus-specific probe for the MBP gene (18q23). Though the patient appeared to have normal chromosome 18s by repeated high resolution banding analysis, his clinical features were suggestive of a deletion of 18q. These included hearing loss secondary to stenosis of the external auditory canals, abnormal facial features, and foot deformities. FISH studies with genomic probes from 18q22.3 to 18qter confirmed a cryptic deletion which encompassed the MBP gene. In an attempt to further characterize the deletion, whole genome screening was conducted using array based comparative genomic hybridization (array CGH) analysis. The array CGH data not only confirmed a cryptic deletion in the 18q22.3 to 18qter region of approximately 7 Mb, it also showed a previously undetected 3.7 Mb gain of 4q material. FISH studies demonstrated that the gained 4q material was translocated distal to the 18qter deletion breakpoint. The 18q deletion contains, in addition to MBP, other known genes including CYB5, ZNF236, GALR1, and NFATC1, while the gained 4q material includes the genes FACL1 and 2, KLKB1, F11 and MTNR1A. The use of these combined methodologies has resulted in the first reported case in which array CGH has been used to characterize a congenital chromosomal abnormality, highlighting the need for innovative molecular cytogenetic techniques in the diagnosis of patients with idiopathic neurological abnormalities. © 2003 Wiley-Liss, Inc.

Most individuals with constitutional deletions of chromosome 18q have developmental delays, dysmyelination of the brain, and growth failure due to growth hormone deficiency. We monitored the effects of growth hormone treatment by evaluating 23 individuals for changes in growth, nonverbal intelligence quotient (nIQ), and quantitative brain MRI changes. Over an average of 37 months, the treated group of 13 children had an average nIQ increase of 17 points, an increase in height standard deviation score of 1.7, and significant change in T1 relaxation times in the caudate and frontal white matter. Cognitive changes of this magnitude are clinically significant and are anticipated to have an effect on the long-term outcomes for the treated individuals.

This article reports a gender replication study of the P. T. Fox et al. (2000) performance correlation analysis of neural systems that distinguish between normal and stuttered speech in adult males. Positron-emission tomographic (PET) images of cerebral blood flow (CBF) were correlated with speech behavior scores obtained during PET imaging for 10 dextral female stuttering speakers and 10 dextral, age- and sex-matched normally fluent controls. Gender comparisons were made between the total number of voxels per region significantly correlated with speech performance (as in P. T. Fox et al., 2000) plus total voxels per region that were significantly correlated with stutter rate and not with syllable rate. Stutter-rate regional correlates were generally right-sided in males, but bilateral in the females. For both sexes the positive regional correlates for stuttering were in right (R) anterior insula and the negative correlates were in R Brodmann area 21/22 and an area within left (L) inferior frontal gyrus. The female stuttering speakers displayed additional positive correlates in L anterior insula and in basal ganglia (L globus pallidus, R caudate), plus extensive right hemisphere negative correlates in the prefrontal area and the limbic and parietal lobes. The male stuttering speakers were distinguished by positive correlates in L medial occipital lobe and R medial cerebellum. Regions that positively correlated with syllable rate (essentially stutter-free speech) in stuttering speakers and controls were very similar for both sexes. The findings strengthen claims that chronic developmental stuttering is functionally related to abnormal speech-motor and auditory region interactions. The gender differences may be related to differences between the genders with respect to susceptibility (males predominate) and recovery from chronic stuttering (females show higher recovery rates during childhood).

To investigate the use of a three-pool relaxation model to measure myelin, myelinated-axon, and mixed water-pool fractions in white matter (WM) during myelination.MRI at 1.9 Tesla, and conventional spin-echo imaging were used to acquire T1 and T2 relaxation data in 15 normal children ranging in age from 3 months to 13 years 4 months. Three equations with three unknowns were solved to calculate three water-pool fractions for each child in a frontal association-fiber area and a frontal-parietal projection-fiber area. The temporal trend of the fractions was compared with a theoretical three-pool myelination model.The myelin level in the projection-fiber area rose earlier than in the association-fiber area following the standard caudal-to-rostral trend. The temporal trend of the three-pool fractions followed that predicted by the theoretical myelination model in both brain areas. The myelinated-axon and mixed pool sizes were significantly different in the two WM areas following early myelination, although their myelin pools were similar. T1 values correlated more highly with the myelinated-axon and mixed pool fractions than with the myelin pool fraction.The three-pool relaxation model provides measurements of water-pool fractions in WM that follow values predicted during myelination.