Amelioration of the typical cognitive phenotype in a patient with the 5pter deletion associated with Cri-du-chat syndrome in addition to a partial duplication of CTNND2.

Cri-du-chat is a rare congenital syndrome characterized by intellectual disability, severe speech/developmental delay, dysmorphic features, and additional syndromic findings. The etiology of this disorder is well known, and is attributed to a large deletion on chromosome 5 that typically ranges from band 5p15.2 to the short arm terminus. This region contains CTNND2, a gene encoding a neuronal-specific protein, delta-catenin, which plays a critical role in cellular motility and brain function. The exact involvement of CTNND2 in the cognitive functionality of individuals with Cri-du-chat has not been fully deciphered, but it is thought to be significant. This report describes an 8-year-old African-American female with a complex chromosome 5 abnormality and a relatively mild case of cri-du-chat syndrome. Because of the surprisingly mild cognitive phenotype, although a karyotype had confirmed the 5p deletion at birth, an oligo-SNP microarray was obtained to further characterize her deletion. The array revealed a complex rearrangement, including a breakpoint in the middle of CTNND2, which resulted in a partial deletion and partial duplication of that gene. The array also verified the expected 5p terminal deletion. Although the patient has a significant deletion in CTNND2, half of the gene (including the promoter region) is not only preserved, but is duplicated. The patient's milder cognitive and behavioral presentation, in conjunction with her atypical 5p alteration, provides additional evidence for the role of CTNND2 in the cognitive phenotype of individuals with Cri-du-chat

Deletion Xq27.3q28 in female patient with global developmental delays and skewed X-inactivation

Abstract Background Global developmental delay and mental retardation are associated with X-linked disorders including Hunter syndrome (mucopolysaccharidosis type II) and Fragile X syndrome (FXS). Single nucleotide mutations in the iduronate 2-sulfatase (IDS) gene at Xq28 most commonly cause Hunter syndrome while a CGG expansion in the FMR1 gene at Xq27.3 is associated with Fragile X syndrome. Gene deletions of the Xq27-28 region are less frequently found in either condition with rare reports in females. Additionally, an association between Xq27-28 deletions and skewed X-inactivation of the normal X chromosome observed in previous studies suggested a primary role of the Xq27-28 region in X-inactivation. Case presentation We describe the clinical, molecular and biochemical evaluations of a four year-old female patient with global developmental delay and a hemizygous deletion of Xq27.3q28 (144,270,614-154,845,961 bp), a 10.6 Mb region that contains >100 genes including IDS and FMR1. A literature review revealed rare cases with similar deletions that included IDS and FMR1 in females with developmental delay, variable features of Hunter syndrome, and skewed X-inactivation of the normal X chromosome. In contrast, our patient exhibited skewed X-inactivation of the deleted X chromosome and tested negative for Hunter syndrome. Conclusions This is a report of a female with a 10.6 Mb Xq27-28 deletion with skewed inactivation of the deleted X chromosome. Contrary to previous reports, our observations do not support a primary role of the Xq27-28 region in X-inactivation. A review of the genes in the deletion region revealed several potential genes that may contribute to the patient’s developmental delays, and sequencing of the active X chromosome may provide insight into the etiology of this clinical presentation

Regions of homozygosity (ROH) derived from the proband in the SNP array.

<p>(<b>A</b>) The cytogenetic location, genomic coordinates (hg19) and sizes of each ROH. (<b>B</b>) Location and size (in Mb) of each ROH on chromosomes 3, 4, 9 and 11.</p

Identification of the 649 bp deletion in the proband.

<p>(<b>A</b>) PCR genotyping of the 649 bp deletion in a normal control (NC), mother (M), father (F) and proband (P). Size markers (M) consist of a 500 bp ladder. The sizes of the amplicons representing the normal (1073 bp) and mutant (424 bp) alleles are indicated next to the gel. (<b>B</b>) Sanger DNA sequencing electropherogram of the mutant amplicon, showing the deletion breakpoint (indicated by the arrow). (<b>C</b>) Representative DNA sequence of the 1073 bp amplicon extending from the forward and reverse primer (shown in red color). The strikethrough bases indicate the deleted DNA sequences and those of exon 2 are highlighted.</p

Additional file 2: Table S1. of Enrichment of small pathogenic deletions at chromosome 9p24.3 and 9q34.3 involving DOCK8, KANK1, EHMT1 genes identified by using high-resolution oligonucleotide-single nucleotide polymorphism array analysis

List of the cases with small (<1 Mb) pathogenic copy number loss on chromosome 9 without involvement of other chromosomes (N = 57). Table S2. List of the remaining cases with copy number loss on chromosome 9 (N = 47). Table S3. Interpretation, references and ClinGen evaluation of haploinsufficiency score of selected cytogenetically relevant genes on chromosome 9. (DOCX 43 kb

Tertiary structure modeling of the mutant HGD protein.

<p>(<b>A</b>) Crystal structure of the normal and (<b>B</b>) tertiary structure model of the mutant HGD protein α-helical coils, β-pleated sheets and interconnecting loops are colored in turquoise, magenta and pink, respectively. In (A), exon 2 is represented by the two yellow anti-parallel β-pleated sheets and green interconnecting loops. The adjoining four amino acids from exons 1 and 3 are shown in blue. Note in (B), the absence of exon 2 β-pleated sheets and loops and the presence of a novel loop (shown in blue) that represents 4 amino acids from each of exons 1 and 3. Despite the similarities of the β-sheets between the two structures, most of the amino acids in the α-helical coils are different from the native structure. This figure does not contain any copyrighted image.</p