11p13 microduplication: a differential diagnosis of Silver-Russell syndrome?

BACKGROUND: Silver-Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging. CASE PRESENTATION: A girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver-Russel syndrome. CONCLUSIONS: The identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.

Mosaic Variegated Aneuploidy Syndrome and Noonan Syndrome in the Same Family.

Introduction: Mosaic variegated aneuploidy syndrome 2 (MVA2) and Noonan syndrome (NS) are 2 genetic disorders with overlapping clinical features, including intrauterine growth retardation, dysmorphic features, and heart defects. Whereas NS is a well-known congenital entity, MVA2 is rare, and only a few cases have been reported in the literature. Case Presentation: We report on the molecular findings in 3 patients with short stature phenotypes from the same family. By considering the clinical overlap between the patients, a common cause for the small stature was assumed in the beginning, but by whole exome analysis (WES) it turned out that the phenotypes were caused by different pathogenic variants in CEP57 and PTPN11, respectively. As a result, both MVA2 and NS occurred in the same family. Conclusion: As our example shows, the parallel occurrence of pathogenic alterations in different genes in the same family constitutes a challenge for the interpretation of WES data and has to be considered. The diagnostic workup illustrates the need for a careful anamnesis and molecular documentation in affected and healthy family members. The knowledge on the different molecular causes underlying the features of the affected family members is the basis for personalised therapeutic managements and can avoid unnecessary burden and even contraindicated therapies; while in patients with NS carrying PTPN11 variants growth hormone treatment leads to height increase, patients with MVA2 carrying CEP57 probably do not benefit from it.

A Genetic Association Study of a Specific Gene and Severe Form of Resorption in the Edentulous Mandible in the Egyptian Population.

PURPOSE: To investigate for the first time in Egypt and the Middle East the relationship between a specific gene and the presence of severely resorbed edentulous mandibular ridges in a sample of the Egyptian population. MATERIALS AND METHODS: The study was conducted on 50 subjects divided into case and control groups according to the residual ridge height. Saliva was used as a convenient source of DNA in the dental clinic. A certain genetic variation (1772C>T) in an important gene related to bone healing (hypoxia-inducible factor-1 alpha [HIF1-α] gene) was selected. The genetic variation 1772C>T is a single nucleotide polymorphism (SNP) that occurs when corresponding sequences of DNA from different individuals differ at one base. Then, we have 2 forms of the gene (2 alleles): C and T. SNPs typically have 3 genotypes; in this study, they are the CC, CT, and TT genotypes. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) was the method performed for genotyping. The statistical significance of the results was evaluated by the Chi-square test and Fisher Exact test. RESULTS: A statistically significant difference in the distribution of the TT genotype between both groups was detected with p-value = 0.049. There was also a difference in the distribution of the CC and CT genotypes, but it was not statistically significant, since the p-values were 0.733 and 0.145, respectively. The T alleles were more abundant in the case group, while the control group showed more frequency of the C allele with no statistical significance. CONCLUSION: The TT genotype of the 1772C>T polymorphism of HIF1-α gene is related to the presence of severely atrophied residual ridges in completely edentulous Egyptians. This can be used as a marker to predict the future condition of the ridge using saliva samples. Further studies on larger scale are recommended.

Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes.

LBR (Lamin B Receptor) encodes a bifunctional protein important for cholesterol biosynthesis and heterochromatin organization on the inner nuclear membrane. Pathogenic variants in LBR are associated with marked phenotypic variability, ranging from the benign Pelger-Huët anomaly to lethal Greenberg Dysplasia. We performed trio exome sequencing (ES) on two patients with atypical variants of skeletal dysplasia and their unaffected parents. Patient 1 exhibited frontal bossing, mid-face hypoplasia, short stature with rhizomelic limb shortening, and relative macrocephaly at birth. Although remained short, Patient 1 later showed spontaneous improvement in her skeletal findings. Exome sequencing revealed two novel variants in LBR, c.1504C > G (p.Arg502Gly) in exon 12 and c.1748G > T (p.Arg583Leu) in exon 14, which were inherited from her unaffected father and mother, respectively. Sterol analysis revealed an increased level of cholesta­8,14­dien­3ß­ol to 2.9% of total sterols, consistent with a functional deficiency of 3ß­hydroxysterol Δ14­reductase. Patient 2 presented at birth with short stature and marked rhizomelic limb shortening but later exhibited decreasing severity of shortening of the long bones and improvement in the radiographic skeletal abnormalities although he continued to be significantly short at age 10 years. Exome sequencing revealed that Patient 2 is homozygous for a pathogenic variant c.1534C > T (p.Arg512Trp) in exon 12 of LBR, which was inherited from his unaffected consanguineous parents. This report provides further evidence for a phenotypic spectrum of LBR-associated disorders and expands the genotypic spectrum by describing 3 novel disease-causing variants that have not been previously associated with a disease. Moreover, our data on Patient 1 demonstrate that variants throughout the gene appear to influence both the sterol reductase and nuclear functions of LBR.