Explore the vast range of titles available.

BackgroundAxial and extra-axial deceleration in function and progressive joint pain with subsequent development of antalgic gait associated with swellings, and stiffness of the joints with loss of the physiological spine biomechanics were the natural history in this group of patients. Clinical and radiological phenotypes have been analysed carefully to further understand the aetiology behind.MethodsSeven patients (three children around the age of 9–11 and one child of 17 years old). Three adults aging 25, 30, 33 and 40 years old were seen and examined. The paediatric group of patients were initially diagnosed with myopathy followed later by juvenile rheumatoid arthritis in other institutions. Clinical and imaging documentation were collected in our departments, followed by mutation screening, was carried out by bidirectional sequencing of the WISP3 gene.ResultsClinical and radiological phenotypic studies confirmed the diagnosis of progressive pseudorheumatoid chondrodysplasia. A constellation of abnormalities such as early senile hyperostosis of the spine (Forestier disease), osteoarthritis of the hips showed progressive diminution and irregularities of the hip joint spaces associated with progressive capital femoral epiphyseal dysplasia and coxa vara have been encountered. Loss-of-function homozygous mutations (c.667T>G, p.Cys223Gly) and (c.170C>A, p.Ser57*) in the WISP3 gene were identified in our patients.ConclusionThe definite diagnosis was not defined via vigorous myopathic and rheumatologic investigations. Detailed clinical examination and skeletal survey, followed by genotypic confirmation, were our fundamental pointers to rule out the false diagnosis of juvenile rheumatoid arthritis and rheumatoid polyarthritis in the adult group of patients. We wish to stress that the clinical/radiological phenotype is the baseline tool to establish a definite diagnosis and to guide the geneticist toward proper genotype.Key Points•Joint pain and difficulties in walking/climbing the stairs are characteristic features encountered in early childhood. False diagnosis of juvenile rheumatoid arthritis can be made at this point.•False positive-like muscular wasting resembling myopathy results in ensuing vigorous troublesome investigations.•Flattened vertebral bodies associated with defective ossification of the anterior end plates are characteristic features of progressive pseudorheumatoid chondrodysplasia.•Joint expansions, which are usually accompanied by narrowing of the articular ends of the appendicular skeletal system, show a clear radiological phenotype of pseudorheumatoid chondrodysplasia.

Background/Objectives: CDH1 gene is widely studied, as pathogenic variants are involved in diffuse gastric cancers and lobular breast cancers. CDH1 genotype contributes to the management of clinical practice recommendations for cancer prevention. We proposed a qualitative and quantitative description of CDH1 alternative splicing profile on lymphoblastoid cell lines (LCLs). The aim of this description was to allow a comprehensive interpretation of the effect of variants of uncertain significance (VUS) on CDH1 splicing. Methods: We studied, using RNAseq, the splicing profile of 22 LCLs (untreated and treated with puromycin) with no pathogenic variant on CDH1 and evaluated the effect on CDH1 splicing of four VUS. Results: We highlighted a total of eleven alternative splicing events including four junctions starting from intron 2, defining novel isoforms of CDH1. We also identified an isoform causing the skip of exon 11 and leading to a disruption of the reading frame with high levels of expression on negative CDH1 control LCLs, confirmed by ddPCR. Splicing RNAseq results for CDH1 VUS: c.1008+1G>A and c.1936+5G>A showed complex splicing patterns but allowed their classification as pathogenic. We studied CDH1 VUS exon 4 to exon 11 duplication with RNA analysis combined with Bionano optical genome mapping. Depending on alternative splicing of proximal and distal exons 11 within the duplication, we identified four distinct transcripts, leading to truncated proteins, classifying the duplication as pathogenic. Conclusions:CDH1 has a complex alternative splicing profile characterized by a dynamic splicing of intron 2 making CDH1 a good candidate for a study using long-read RNAseq.

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.

The high incidence of de novo chromosomal aberrations in a population of persons with autism suggests a causal relationship between certain chromosomal aberrations and the occurrence of isolated idiopathic autism. We report on the clinical and cytogenetic findings in a male patient with autism, no physical abnormalities and a de novo balanced (7;16)(p22.1;p16.2) translocation. G-banded chromosomes and fluorescent in situ hybridization (FISH) were used to examine the patient's karyotype as well as his parents'. FISH with specific RP11-BAC clones mapping near 7p22.1 and 16p11.2 was used to refine the location of the breakpoints. This is, in the best of our knowledge, the first report of an individual with autism and this specific chromosomal aberration.

Nance-Horan Syndrome (NHS) or X-linked cataract-dental syndrome is a disease of unknown gene action mechanism, characterized by congenital cataract, dental anomalies, dysmorphic features and, in some cases, mental retardation. We performed linkage analysis in a Tunisian family with NHS in which affected males and obligate carrier female share a common haplotype in the Xp22.32-p11.21 region that contains the NHS gene. Direct sequencing of NHS coding exons and flanking intronic sequences allowed us to identify the first missense mutation (P551S) and a reported SNP-polymorphism (L1319F) in exon 6, a reported UTR–SNP (c.7422 C>T) and a novel one (c.8239 T>A) in exon 8. Both variations P551S and c.8239 T>A segregate with NHS phenotype in this family. Although truncations, frame-shift and copy number variants have been reported in this gene, no missense mutations have been found to segregate previously. This is the first report of a missense NHS mutation causing NHS phenotype (including cardiac defects). We hypothesize also that the non-reported UTR–SNP of the exon 8 (3′-UTR) is specific to the Tunisian population.

Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor ( ) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We describe a new case of Donohue syndrome born at 37 weeks’ gestation of unrelated parents and presented with intra-uterine growth retardation, nipple hypertrophy, macropenis, distended abdomen, hirsutism and dysmorphic features. The clinical course showed failure to thrive, and episodes of alternating hypoglycemia and hyperglycemia. Laboratory tests revealed direct hyperbilirubinemia. The diagnosis of Donohue syndrome was established based on the above clinical characteristics and determination of the mutation. He was found to have homozygous nonsense mutation c. 2270 C>T (Arg924X) at exon 14 of the gene. He later developed enterocolitis and died at 3 months old. Prenatal diagnosis was performed for the family via chorionic villous biopsy. We try to explain gastrointestinal dysfunction seen in our patient.

PAK3 -related mental retardation represents a rare cause of X-linked mental retardation associated with behavioural symptoms. So far, four families carrying PAK3 mutations have been reported, and in most cases PAK3 dysfunction resulted from missense mutations thought to affect either the catalytic or the N-terminal regulatory domain activity. Here, we report on a Tunisian family of X-linked moderate mental retardation with behavioural symptoms, common dysmorphic features, oro-motor impairment and secondary microcephaly. Linkage analysis showed that affected male subjects and obligate carrier female subjects share a common haplotype in the Xp21.31 – Xq23 region that contains the PAK3 gene. Direct sequencing of PAK3 coding exons and flanking intronic sequences allowed us to identify the first splice mutation in PAK3 gene located at the 5′ end of intron 6 (c.276+4A>G), which results in a complete switch-off of the genuine donor splice site and an activation of a cryptic donor splice site (GTAAG) located four nucleotides downstream to the genuine one. RT-PCR experiments using the RNA from the patient's lymphoblasts showed that PAK3 transcripts contain four additional nucleotides that lead to a disruption of reading frame with a premature stop codon at position 128. Together with previously reported observations, our data further confirm that PAK3 mutations result in a specific form of X-linked mental retardation with fairly constant clinical features.

L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive neurometabolic disorder characterized essentially by the presence of elevated levels of L-2-hydroxyglutaric acid (LGA) in plasma, cerebrospinal fluid and urine. L2HGA is caused by a deficiency in the L2-Hydroxyglutaric dehydrogenase (L2HGDH) enzyme involved in the oxidation of LGA to the alpha 2-ketoglutarate. LGA has been proposed as an endo- and exogenous cytotoxic organic acid that induces free radical formation and generation of reactive oxygen species (ROS). In this report, we analyzed 14 L2HGA patients belonging to six unrelated consanguineous families the south of Tunisia. The patients were diagnosed with L2HGA disease confirmed on the presence of high level of LGA in urine. We analyzed the L2HGDH gene in all probands and identified the same c.241A>G homozygous mutation, which was previously reported in Tunisia. We also used intragenic single nucleotide length polymorphisms (SNPs) and two extragenic microsatellites flanking the L2HGDH gene to confirm the founder effect of c.241A>G mutation in the 14 studied cases. In addition, we carried out the measurement of the oxidative stress parameters in the plasma of L2HGA patients which revealed a significant increase in the malondialdehyde levels (MDA), a biomarker of lipid peroxydation, and the reduced glutathione (GSH). A diminution of the antioxidant enzyme activities including superoxide dismutase (SOD), glutathione peroxidase (GPx), was also observed.

Subtelomeric rearrangements significantly contribute to idiopathic mental retardation and result in several mental retardation syndromes; however, most subtelomeric defects lack a characteristic phenotype. Thirty patients with unexplained mental retardation, a normal R banded karyotype at the 550 band, and no clinically recognizable syndrome were screened by Multiplex ligation-dependent probe amplification (MLPA). Four anomalies were identified: deletion 17q, duplications (4q), and associated duplications 15q and Xq. This duplication was found in two sisters of the proband. Anomalies were unidentified by the conventional technique. The prevalence of subtelomeric imbalances in our cohort of moderate to severe mental retardation is around 13% and is consistent with the literature. The sensitivity of the MLPA technique was characterized on cytogenetically verified positive and negative controls. MLPA is a fast, reliable, and relatively inexpensive technique to detect subtelomeric rearrangement in comparison with the fluorescence in situ hybridization (FISH) technique.

Autism is a complex neurodevelopmental disorder characterized by impairment of social interaction, language, communication, and stereotyped, repetitive behavior. Genetic predisposition to autism has been demonstrated in families and twin studies. About 5–10% of autism cases are associated with chromosomal abnormalities or monogenic disorders. The identification of genes involved in the origin of autism is expected to increase our understanding of the pathogenesis. We report on the clinical, cytogenetic, and molecular findings in a boy with autism carrying a de novo translocation t(7;16)(p22.1;p11.2). The chromosome 16 breakpoint disrupts the paralogous SLC6A8 gene also called SLC6A10 or CT2. Predicted translation of exons and RT-PCR analysis reveal specific expression of the creatine transporter paralogous in testis and brain. Several studies reported on the role of X-linked creatine transporter mutations in individuals with mental retardation, with or without autism. The existence of disruption in SLC6A8 paralogous gene associated with idiopathic autism suggests that this gene may be involved in the autistic phenotype in our patient.