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15q13.3 syndrome is associated with a wide spectrum of neurological disorders. Among a cohort of 150 neurodevelopmental cases, we identified two patients with two close proximity interstitial hemizygous deletions on chromosome 15q13. Using high-density microarrays, we characterized these deletions and their approximate breakpoints. The second deletion in both patients overlaps in a small area containing CHRNA7 where the gene is partially deleted. The CHRNA7 is considered a strong candidate for the 15q13.3 deletion syndrome’s pathogenicity. Patient 1 has cognitive impairment, learning disabilities, hyperactivity and subtle dysmorphic features whereas patient 2 has mild language impairment with speech difficulty, mild dysmorphia, heart defect and interestingly a high IQ that has not been reported in 15q13.3 syndrome patients before. Our study presents first report of such two successive deletions in 15q13.3 syndrome patients and a high IQ in a 15q13.3 syndrome patient. Our study expands the breakpoints and phenotypic features related to 15q13.3 syndrome.

The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad-Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43-44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.

The molecular basis of familial isolated GH deficiency (IGHD) is heterogeneous. We have previously found a G → A transition in codon 20 of the GH gene that produces a stop codon and two donor splice site mutations (a T → C transition in the sixth base of IVSIII and G→ C transversion in the first base of IVS IV). The G→ C transversion, which destroys an HphI (GGTGA) restriction site at the exon IV/intron IV boundary (G/GTGA → G/CTGA), was found in a Saudi family with IGHD. To determine the frequency of this mutation among Saudi IGHD subjects, dried blood spots were analyzed from 12 additional Saudi cases from different families. The methodology involved a one-step PCR amplification of DNA obtained from 2 mm2 portions of dried blood spots which were collected on filter paper. These amplification products were then digested with HphI and analyzed on agarose gels. One subject was homozygous and the single, parental sample obtained was heterozygous for loss of this HphI site. Interestingly a simple repeat polymorphism adjacent to the GH gene differed between the two non-related Saudi subjects, who lacked the HphI site, suggesting that the GH mutaiions were independent. To determine if the GH mutations causing loss of the HphI site differed between the two Saudi IGHD cases, direct sequencing of the PCR products obtained from the filler paper samples was performed. In contrast 10 the firsi Saudi case which had a G→C transversion in the first base of IVS IV (G/CTGA) the second had a G→T transversion (G/TTGA). Analysis of the transcription products of the G→C mutation documented aberrant splicing and transcript analysis of the G→T mutation is being done for comparison. Our findings demonstrate 1) detection of GH splicing defects by restriction analysis and sequencing of DNA from dried blood spots and 2) 2/13 (15%) of Saudi IGHD subjects have IVS 3V donor splice site defects. These findings suggest that heterogeneous mutations which lead to transcript splicing errors may constitute a significant proportion of IGHD cases.