Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies.

Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute threshold below which signs of FXS present. Since FMR1 expression is known to be highly variable between unrelated females, and since FMR1 mRNA levels have been suggested to be more similar among family members, we further explored the possibility of an intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were significantly lower than in their respective mothers, which was shown to be specific for patients with microdeletions containing FMR1.

Familial translocation t(6;20)(p21;p13) resulting in partial trisomy 6p and partial monosomy 20p: report of a new case and review of the literature.

Carriers of completely balanced chromosomal translocations have all necessary genetic information. Nevertheless, because of the possibility of maldistribution during gametogenesis, they are at increased risk for infertility, miscarriage, stillbirth or having a child with congenital anomalies including mental retardation. As postnatal clinical reports are infrequent, prediction of clinical course for specific unbalanced karyotypes diagnosed during pregnancy remains difficult. Here, we report the 6th case of partial trisomy 6p and partial monosomy 20p due to an unbalanced adjacent-1 segregation of the rare familial translocation t(6;20)(p21;p13). We give a thorough clinical description of the present case, demonstrating broad phenotypic overlap with the 5 previously published cases reviewed here, providing important data on postnatal outcome.

5q31 Microdeletions: Definition of a Critical Region and Analysis of LRRTM2, a Candidate Gene for Intellectual Disability.

Microdeletions including 5q31 have been reported in only few patients to date. Apart from intellectual disability/developmental delay (ID/DD) of varying degrees, which is common to all reported patients, the clinical spectrum is wide and includes short stature, failure to thrive, congenital heart defects, encephalopathies, and dysmorphic features. We report a patient with a 0.9-Mb de novo deletion in 5q31.2, the smallest microdeletion in 5q31 reported thus far. His clinical presentation includes mild DD, borderline short stature, postnatal microcephaly, and mild dysmorphic signs including microretrognathia. Together with data from 7 reported overlapping microdeletions, analysis of our patient enabled the tentative delineation of a phenotype map for 5q31 deletions. In contrast to the mild phenotype of small microdeletions affecting only 5q31.2, carriers of larger microdeletions which also include subbands 5q31.1 and/or 5q31.3 seem to be more severely affected with congenital malformations, growth anomalies, and severe encephalopathies. A 240-kb smallest region of overlap in 5q31.2 is delineated which contains only 2 genes, CTNNA1 and LRRTM2. We propose LRRTM2 as the most promising candidate gene for ID/DD due to its expression pattern, function as a key regulator of excitatory development, and interaction with Neurexin 1. However, sequence analysis of LRRTM2 in 330 patients with ID/DD revealed no relevant alterations, excluding point mutations in LRRTM2 as a frequent cause of ID/DD in patients without microdeletions.