SPG20 mutation in three siblings with familial hereditary spastic paraplegia

Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the SPG20 gene, encoding spartin, on Chromosome 13q13. Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability. Targeted exon capture and sequencing showed a homozygous nonsense mutation in the SPG20 gene, c.1369C>T (p.Arg457*), in the three affected boys.status: publishe

Hereditary neuropathy with liability to pressure palsies

status: publishe

Genotype-phenotype correlations of UBA2 mutations in patients with ectrodactyly

Interstitial 19q13.11 deletions are associated with ectrodactyly, which has recently been linked to loss-of-function of the UBA2 gene. We report a boy with a de novo frameshift mutation in UBA2 (c.612delA (p.(Glu205Lysfs*63)), presenting with ectrodactyly of the feet associated with learning difficulties and minor physical anomalies. We review genotype-phenotype correlations in patients with chromosomal 19q13.11 microdeletions compared to those with intragenic UBA2 mutations.status: publishe

DETECTION OF FACIAL DYSMORPHISM IN CENTRAL AFRICAN PATIENTS

INTRODUCTION AND METHODS Recent advances in morphometric analysis have explored the possibility to perform an objective evaluation of the facial gestalt from 2D or 3D facial images and find a reliable syndrome match. This requires matching the face of a patient with similar patients in a database of individuals with known syndromes (Hammond, Hutton et al. 2005; Ferry, Steinberg et al. 2014). Such a user-friendly tool holds great promise of reaching a rapid diagnosis for common genetic syndromes. Especially in low resource countries, where access to laboratory testing is limited, the potential of such a tool is great. Studying dysmorphism in Central Africa is challenging, because the facial morphology in normal individuals presents obvious differences between African and other populations (Talbert, Kau et al. 2014). In addition, the craniofacial presentation of some syndromes in a patient of African origin may differ from a Caucasian with the same syndrome as showed for the del22q11, Fragile X and fetal alcohol syndromes (McDonald-McGinn et al. 2005; Schwartz, Phelan et al. 1988; Moore, Ward et al. 2007). We aimed to assess the performance of the existing computed phenotyping tool Face2Gene, at the current stage of its development, to recognize Down syndrome in Congolese versus Caucasian patients. The study is part of an etiological diagnostic study in 127 patients with intellectual disability, recruited in 6 specialized clinics and schools in Kinshasa in the DR Congo. We uploaded to Face2Gene the facial photographs of 17 DS patients from Congo and 20 DS patients from Flanders in Belgium. Patients from the 2 groups were sex and age matched. Our research protocol was approved by the Ethical Committee of the University of Kinshasa, Kinshasa, the DR Congo. RESULTS Face2Gene reported DS match within the first 10 matches in 16 (80 %) Belgian patients but only in 7 (35.29 %) Congolese patients. In Congolese patients, Down syndrome was the first suggested match in 2, ranked within the first 5 matches in 5 and within the first 10 in 6 of them. Conversely, Down syndrome was the first suggested match in 8, ranked within the first 5 matches in 13 and within the first 10 in 17 of them in the 20 Flemish cases. The mean rank in the Congolese patients was 8.29, which is significantly lower than the mean 4.65 recorded from Europeans (p = 0.004446 ± 0.000674). Altogether, Face2Gene showed an Accuracy of 0.35 in Congolese against 0.8 in Belgians and a Precision of 1 in both groups. DISCUSSION Our data indicate that the system has a high precision in both groups. However, the accuracy in the Caucasian cohort was much higher compared to the African cohort. This is interesting, since it confirms that there are differences in facial appearance of Caucasian versus African Down syndrome patients. The most likely explanation why Face2gene is underperforming in Congolese Down syndrome is that the tool is trained mostly with Caucasian cases. We therefore anticipate that the performance will improve when the system is trained with more Down syndrome cases from Central Africa. A collaborative effort to test this hypothesis is ongoing. Likewise, we expect that the efficiency of Face2Gene might improve if an increasing number of cases with a known diagnosis are uploaded

Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of FOXG1 appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus

BackgroundDeletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype-phenotype correlation by accurately determining the size and location of the deletions and the associated phenotype.MethodsHere the authors report the molecular karyotyping and phenotypic description of seven patients with overlapping deletions including chromosome 14q13.ResultsThe authors show that deletions including 14q13 result in a recognisable phenotype mainly due to haploinsufficiency of two genes (NKX2-1, PAX9). FOXG1 (on chromosome band 14q12) involvement seems to be the main determinant of phenotype severity. The patients in this study without FOXG1 involvement and deletions of up to 10 Mb have a relatively mild phenotype. The authors cannot explain why some patients in literature with overlapping but smaller deletions appear to have a more severe phenotype. A previously presumed association with holoprosencephaly could not be confirmed as none of the patients in this series had holoprosencephaly.ConclusionsFOXG1 appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded.status: publishe

Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males due to the hemizygous state of their X chromosome. Carrier females are generally unaffected due to the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analysed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (> 90%), which is significantly higher than observed in the general population (3.6%; p = 0.029). Whole exome sequencing of 19 females with extreme skewing revealed causal variants in 6 females in the XLID genes DDX3X, NHS, WDR45, MECP2 and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in 3 of these patients. Moreover, variants likely accounting for skewing only, were detected in MED12, HDAC8 and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients. This article is protected by copyright. All rights reserved.status: publishe

Identification of intellectual disability genes in female patients with a skewed X-inactivation pattern

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males due to the hemizygous state of their X chromosome. Carrier females are generally unaffected due to the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analysed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; p=0.029). Whole exome sequencing of 19 females with extreme skewing revealed causal variants in 6 females in the XLID genes DDX3X, NHS, WDR45, MECP2 and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in 3 of these patients. Moreover, variants likely accounting for skewing only, were detected in MED12, HDAC8 and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients