No abstract

As a result of the increasing use of genome wide telomere screening, it has become evident that a significant proportion of people with idiopathic mental retardation have subtle abnormalities involving the telomeres of human chromosomes. However, during the course of these studies, there have also been telomeric imbalances identified in normal people that are not associated with any apparent phenotype. We have begun to scrutinise cases from both of these groups by determining the extent of the duplication or deletion associated with the imbalance. Five cases were examined where the telomere rearrangement resulted in trisomy for the 16p telomere. The size of the trisomic segment ranged from ∼4-7 Mb and the phenotype included mental and growth retardation, brain malformations, heart defects, cleft palate, pancreatic insufficiency, genitourinary abnormalities, and dysmorphic features. Three cases with telomeric deletions without apparent phenotypic effects were also examined, one from 10q and two from 17p. All three deletions were inherited from a phenotypically normal parent carrying the same deletion, thus without apparent phenotypic effect. The largest deletion among these cases was ∼600 kb on 17p. Similar studies are necessary for all telomeric regions to differentiate between those telomeric rearrangements that are pathogenic and those that are benign variants. Towards this goal, we are developing "molecular rulers" that incorporate multiple clones at each telomere that span the most distal 5 Mb region. While telomere screening has enabled the identification of telomere rearrangements, the use of molecular rulers will allow better phenotype prediction and prognosis related to these findings. U nbalanced submicroscopic telomere rearrangements are a significant cause of idiopathic mental retardation with or without congenital malformations, accounting for approximately 5% of these cases. [1][2][3][4][5][6][7] With the development of a second generation set of telomere specific clones, 8 telomere screening is now readily available in many laboratories and is being used extensively in the evaluation of children with mental retardation and congenital anomalies. The results of these investigations are not only providing explanations for previously unexplained cases of mental retardation, but are also further defining the frequency of telomeric rearrangements in various clinical populations and clarifying the phenotype associated with these rearrangements. Furthermore, during the course of these studies, telomeric imbalances have also been identified in normal subjects without any apparent phenotype.3 5 6 9 These observations suggest that not all telomere imbalances result in a phenotype and that the lack of phenotypic effect may be related to the size of the rearrangement or the involvement of regions of the genome that are tolerant to dosage imbalances.Despite these advances, there is a paucity of information regarding the genotype/phenotype correlations of many of the telomere imbalances discovered, complicating t...

Kabuki syndrome is associated with abnormalities in multiple organ systems. While many of the anomalies are congenital malformations, other clinical manifestations may not appear until later in childhood. Among these associated conditions, autoimmune abnormalities have been described in several patients. These include idiopathic thrombocytopenic purpura (ITP), hemolytic anemia, thyroiditis, and vitiligo. In this report, we describe five affected patients with autoimmune manifestations. Four patients had ITP, and two of these patients had concurrent hemolytic anemia. The fifth patient had vitiligo. Two of the patients with ITP had a chronic and relapsing course. Of note, some of these patients also had hypogammaglobulinemia. The autoimmune disorders may be manifestations of abnormal immune regulation. We conclude that Kabuki syndrome is associated with an increased incidence of autoimmune disorders. In addition, the presence of an underlying immune defect may predispose these children to a chronic course of these autoimmune conditions.

The Cornelia de Lange syndrome (CdLS) is an autosomal dominant multisystem disorder characterized by somatic and cognitive retardation, characteristic facial features, limb abnormalities, hearing loss, and other organ system involvement. The vast majority of cases (99%) are sporadic, with rare familial occurrences having been reported. Most individuals with CdLS do not reproduce as a result of the severity of the disorder. Maternal transmission has been well documented, as have several cases of multiple-affected children being born to apparently unaffected parents. Paternal transmission has rarely been reported. A case is reported here of a father with classic features of CdLS with a similarly affected daughter. A review of the reported familial cases of CdLS is summarized.

Kabuki (Niikawa-Kuroki) syndrome is associated with growth retardation, developmental delay, congenital heart disease, cleft palate, and characteristic facial features. Although the external appearance of the eyes has been well-described, the type and frequency of structural and functional eye anomalies has not been emphasized. We report three children with Kabuki syndrome who also had a retinal coloboma. A diagnosis of CHARGE association was initially suggested in two of the patients before the typical facial features of Kabuki syndrome emerged. A detailed review of reported cases of Kabuki syndrome shows that a variety of eye anomalies are associated with Kabuki syndrome. The incidence of coloboma is greatly increased in Kabuki syndrome. Thus, ophthalmologic abnormalities are frequently associated with Kabuki syndrome, and an ophthalmologic evaluation should be performed for each patient. Phenotypic overlap, including congenital heart, ear, and renal defects, can lead to the diagnosis of CHARGE association, especially since the typical facial features of Kabuki syndrome may not be apparent in early infancy. Thus, Kabuki syndrome should be considered in patients with coloboma if other features consistent with this condition are present, and follow-up evaluations are indicated for establishing the proper diagnosis.

BackgroundSeveral electroporation protocols exist to transfect exogenous DNA into Plasmodium falciparum. To date, however, only a subjective analysis of their relative efficiencies has been reported.MethodsA time-course of luciferase reporter expression is used to provide an objective quantitative analysis of the absolute efficiency of three electroporation techniques; direct electroporation of ring stage infected erythrocytes, preloading of erythrocytes and a novel “double-tap” protocol that combines both approaches.ResultsPreloading of erythrocytes shows a mean efficiency of 9.59x10-6, some 5–180 fold more efficient than matched experiments utilizing the “double-tap” and direct electroporation of ring stage infected erythrocytes alone, respectively.ConclusionEvidence presented here provides the first quantitative assessment of both the absolute and relative efficiencies of a key molecular tool used to study the biology and pathogenesis of this important human pathogen.

Autosomal dominant myoclonus-dystonia syndrome (MDS) is characterized by myoclonic and/or dystonic movements with onset as early as infancy. In most families, MDS is caused by mutations in the gene SGCE, which encodes epsilon -sarcoglycan and is located on chromosome 7q21. Data from several sources, including multi-generation pedigrees revealing parent-of-origin effects on MDS penetrance, suggest that SGCE is maternally imprinted. We present a 32-month-old patient with an interstitial deletion affecting chromosome 7q21, and a phenotype including myoclonus, microcephaly, short stature, dysmorphic face and language delay. We used fluorescence in situ hybridization (FISH) to estimate the size of our patient's deletion (9.0-15 Mbp) and to confirm absence of SGCE on the affected chromosome. Polymerase chain reaction (PCR) analysis of polymorphic markers in the region revealed that the paternally inherited chromosome contained the deletion, consistent with a model of maternal SGCE imprinting. Our patient is the first case of MDS caused by complete deletion of SGCE, and represents a new contiguous gene disorder. The case underscores the need to consider chromosomal deletions in patients whose phenotypes are more complex than the classic presentation of a known disease.

We present three families with infantile myofibromatosis (IM; OMIM no. 228550) inherited in an autosomal dominant (AD) manner. These three pedigrees prompted re-assessment of pedigrees available within the genetic, oncologic, surgical, and pathologic literature, which suggest autosomal recessive (AR) inheritance. All familial IM may be interpreted as AD or, alternatively, there may be genetic heterogeneity for IM. As most nodules tend to regress spontaneously, familial history may be difficult to obtain and/or confirm. Clinical diagnosis and establishment of inheritance pattern can be important for prognosis and the recognition that other family members may be affected.