Homozygous indel mutation in CDH11 as the probable cause of Elsahy-Waters syndrome.

Two sisters from a consanguineous couple were seen in genetics department for facial dysmorphic features and glaucoma. They both had broad foreheads, hypertelorism, megalocorneas, thick eyebrows with synophrys, flat malar regions, broad and bulbous noses, and mild prognathism. Both had glaucoma, younger one also had cataracts and phthisis bulbi. Other findings included bilateral partial cutaneous syndactyly of 2nd and 3rd fingers, history of impacted teeth with dentigerous cyst in the elder one, and intellectual disability (mild and borderline). The sisters were considered to have Elsahy-Waters syndrome. In order to elucidate the underlying molecular cause, sisters and their healthy parents were genotyped by SNP arrays, followed by homozygosity mapping. Homozygous regions were further analyzed by exome sequencing in one affected individual. A homozygous indel variant segregating with the condition was detected in CDH11 (c.1116_1117delinsGATCATCAG, p.(Ile372MetfsTer9)), which was then validated by using Sanger sequencing. CDH11 encodes cadherin 11 (osteo-cadherin) that regulates cell-cell adhesion, cell polarization and migration, as well as osteogenic differentiation. Further experiments revealed that CDH11 expression was decreased in patient-derived fibroblasts as compared to the heterozygous parent and another healthy donor. Immunostaining showed absence of the protein expression in patient fibroblasts. In addition, cell proliferation rate was slow and osteogenic differentiation potential was delayed. We consider that this study reveals loss-of-function mutations in CDH11 as a probable cause of this phenotype. Next generation sequencing in further patients would both prove this gene as causative, and finely delineate this clinical spectrum further contributing in identification of other possibly involved gene(s).

WAGR syndrome with tetralogy of Fallot and hydrocephalus.

Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome occurs sporadically due to deletion of chromosome 11p13. A variety of other abnormalities involving different systems have been reported in patients with WAGR syndrome. We report on a patient with WAGR syndrome with accompanying tetralogy of Fallot and hydrocephalus.

Cryptic trisomy 5q35.2qter and deletion 1p36.3 characterised using FISH and array-based CGH.

A 10(6/12)-year-old boy was referred to the genetics department because of mental retardation and dysmorphic findings including microcephaly, flat face, down-slanting palpebral fissures, strabismus, prominent ears, bulbous nasal tip, down-turned corners of the mouth, narrow palate, clinodactyly of the fifth fingers and generalised eczema. Cytogenetic analysis revealed a karyotype of 47,XY,+mar of paternal origin. Multicolour FISH showed the marker chromosome to be derived from chromosome 15. For further elucidation of the phenotype, array-based comparative genomic hybridisation (aCGH) was performed, which revealed dup(5)(q35.2qter) and del(1)(p36.3). Parental FISH analysis revealed that the translocation occurred de novo. Despite the presence of a clinical phenotype along with a microscopically visible chromosomal aberration, a complex cryptic cytogenetic abnormality was causative for the phenotype of the patient. Elucidation of this complex aberration required combination of the whole cytogenetic toolbox.

Bilateral anterior segment dysgenesis in an infant with partial trisomy 16q and partial monosomy 3p.

Anterior segment dysgenesis comprises a spectrum of malformations arising from faulty neural crest cell migration. We report a newborn boy with partial trisomy 16q and partial monosomy 3p who presented with anterior segment dysgenesis with iris hypoplasia on the right and glaucoma on the left in association with systemic anomalies. The anterior segment dysgenesis features observed in this case have not been previously associated with partial trisomy 16q or partial monosomy 3p. Our findings support the hypothesis that an additional anterior segment dysgenesis gene may reside on chromosome 3p or 16q.

Derivative chromosome 1 and GLUT1 deficiency syndrome in a sibling pair.

BACKGROUND: Genomic imbalances constitute a major cause of congenital and developmental abnormalities. GLUT1 deficiency syndrome is caused by various de novo mutations in the facilitated human glucose transporter 1 gene (1p34.2) and patients with this syndrome have been diagnosed with hypoglycorrhachia, mental and developmental delay, microcephaly and seizures. Furthermore, 1q terminal deletions have been submitted in the recent reports and the absence of corpus callosum has been related to the deletion between C1orf100 and C1orf121 in 1q44. RESULTS: This study reports on a sibling pair with developmental delay, mental retardation, microcephaly, hypotonia, epilepsy, facial dysmorphism, ataxia and impaired speech. Chromosome analysis revealed a derivative chromosome 1 in both patients. FISH and MCB analysis showed two interstitial deletions at 1p34.2 and 1q44. SNP array and array-CGH analysis also determined the sizes of deletions detailed. The deleted region on 1p34.2 encompasses 33 genes, among which is GLUT1 gene (SLC2A1). However, the deleted region on 1q44 includes 59 genes and distal-proximal breakpoints were located in the ZNF672 gene and SMYD3 gene, respectively. CONCLUSION: Haploinsufficiency of GLUT1 leads to GLUT1 deficiency syndrome, consistent with the phenotype in patients of this study. Conversely, in the deleted region on 1q44, none of the genes are related to findings in these patients. Additionally, the results confirm previous reports on that corpus callosal development may depend on the critical gene(s) lying in 1q44 proximal to the SMYD3 gene.