Relationship Between Long Arm Duplication of X Chromosome and Lysosomal Storage Disease

Lysosomal storage disorders (LSDs) are rare genetic and clinically heterogeneous metabolic disorders. Despite years of work on the genetic and molecular basis of these diseases, little is still known about their pathology. However, it is mostly inherited autosomal recessively, but three show X-linked inheritance. Copies of the long arm of the X chromosome are very rare, especially in males. Here, we reported a duplication of the q22.3 region of the X chromosome in a male individual in cytogenetic analysis with peripheral blood lymphocyte cultures. Our Finding shows that although the history of Xq duplications in men is limited, as confirmed in the literature review, the duplication in the current case may be associated with LSD and may be helpful to better understand the expression of X-linked traits.

Lysosomal storage disorders are a rare, genetically and clinically heterogeneous group of metabolic disorders. Mutations in lysosomal genes cause gradual accumulation of substrate, cell dysfunction, and cell death within the lysosome. Lysosomal storage diseases affect approximately 1 in 5,000-8,000 individuals worldwide. Most of these diseases are autosomal recessive inherited more than 50 disease groups. Currently, it is known that mutations in more than 70 genes disrupt lysosomal metabolism, leading to neuropathological effects, musculoskeletal abnormalities, dysmorphia, and seizure formation. Diagnosis of LSDs is made according to tests such as clinical symptoms, enzymatic analysis and single gene sequencing [1]. The most common lysosomal storage disorder is Gaucher disease. Most LSDs are inherited in an autosomal recessive fashion. Only three of these diseases; The disease Fabry disease, Hunter disease, and Danon disease are inherited as an X-linked recessive [2]. Fabry disease is caused by mutations in the GLA gene located in the q22.1 region of the X chromosome, resulting in a mutant α-galactosidase-A enzyme. In the literature, cytogenetic findings of this disease are almost nonexistent. The available studies are only molecular findings.  In this study, we present a male individual with lysosomal storage disease with de novo Xq duplication, defined cytogenetically as 46, XY, dup (X) (q22.3), and review the literature.

Metaphase chromosome analysis from peripheral blood lymphocyte cultures and GTG-banding were performed using standard protocols. The karyotype was interpreted as 46, XY, dup (X) (q22.3) (Figure 1). The maternal karyotype was normal, indicating a de novo origin for the dup(X) in the proband.

Chromosome

The study of chromosomes or cytogenetic analysises are a reliable way to help diagnose diseases, plan treatment, or evaluate the effectiveness of treatment. We report a male patient with lysosomal storage disease with duplication of the long arm of the X chromosome at region 22.3. This observed chromosomal aberration is the first cytogenetic finding found in lysosomal storage patients. It is important in this respect. LSDs are generally inherited autosomal recessively, but only three are X-linked recessively (q22.1 region). In the present patient, the duplication on the long arm of the X chromosome appears to be consistent with the X-linked recessive inheritance pattern of the disease. Chromosome Xq duplication is the presence of an extra copy of the genetic material found on the long arm of the X chromosome in each cell.Intrachromosomal duplication or unbalanced X/Y or X/autosome translocation can cause Xq duplications. Duplicates can affect phenotype by changing gene dosage, i.e. extra genes lead to excess proteins. We could not find a similar case in the literature. At the same time, the disease-associated X-linked recessive gene is located in the q22.1 region, whereas we found the damaged region in the q22.3 region of the chromosome. It is quite interesting that the damaged region is in an advanced region of the known chromosome region. In this case, it is thought that there may be new genes related to the disease in the X(q22.3) region or that the duplication found may affect the expression of the known related gene in the q22.1 region.In addition, duplication increases the expression of the gene/genes while reducing how it causes disease or that possible gene/genes in this region may be permutated.

Xq duplications refer to chromosomal disorders resulting from involvement of the long arm of the X chromosome. Prevalence of Xq duplications remains unknown. In general, long arm copies of the X chromosome are rare in males. In most cases, the chromosomal abnormality is X-linked and often inherited from the mother. Classical X-linked disorders are usually a vertical form of inheritance, in which heterozygous females pass the allele on to their sons and daughters. Daughters of affected men are always heterozygous, and sons of affected men are always normal. The vast majority of mutations in X-linked genes cause disease in males only. However, many of the X-linked diseases show different rates of penetrance and expressivity in both genders. In some conditions, such as Fabry disease, heterozygotes are usually affected. The a-galactosidase A gene consists of seven exons located on the X (q22.1). Over 250 mutations have been described in all seven exons, the majority of which are missense point mutations. Isolated duplications of the long arm of the X chromosome are rare, and approximately 60 cases have been reported in the literature [3,4]. The abnormal phenotypes associated with these duplications are usually associated with gene dosage in the duplication site. Most of these were duplications of the Xq12→ q24 or Xq26.3→ qter region [5-13]. Among these duplications, Xq21→ Xq24 duplications were reported in two patients and proximal duplication in three male patients: Xq21→ q22 [14-18]. 

Bulduğumuz duplikasyon da bu bölgeler arasında yer alıyor. Clinical manifestations widely vary depending on the gender of the patient and on the gene content of the duplicated segment. Dysfunction of genes can affect the phenotype. In general, males are typically more severely affected than females. Chromosome Xq duplication syndromes are typically inherited in an X-linked fashion and affect new-born children. This syndrome is a rare congenital defect and symptoms may appear at birth or afterward. Men with duplications of the long arm of the X chromosome often have significant mental retardation and birth defects resulting from functional disomy of the duplicated regions. Most females with Xq copies have normal phenotypes. However, this damage is detected after the birth of an abnormal boy. Such children have been reported in females with phenotypic abnormalities such as short stature, microcephaly, developmental delay/mental retardation, and gonadal dysgenesis. The causes of variability in phenotype have been reported to be due to the size or location of the copied segment, random X inactivation, duplication of dose-sensitive genes and genes that normally escape inactivation, and incomplete inactivation of a portion of the replicated segment [19,20].Although each LSD results from mutations in a different gene and deficiency in enzyme activity or protein function, all LSDs share a common feature in that they result in the accumulation of normally degraded substrates within lysosomes. Many of the LSD genes have been characterized and it is assumed that there are different mutations, in part, within the same gene. However, genotype-phenotype correlations are not always valid. For example, in Gaucher disease, sometimes there may be significant differences in the clinical picture of the disease between siblings, and in some cases one sibling is severely affected while the other has almost no signs of the disease [21]. Apart from genetic and environmental factors, it is thought that some other factors probably play a role in the progression of the disease. While most X-linked diseases show different rates of penetration and expression in both sexes, the vast majority of mutations in X-linked genes cause disease in males only [22]. 

Although date on Xq duplications in males are limited, there appears to be an association between duplication and lysosomal storage disease, as demonstrated in the present case. However, it can be said that there may be a relationship between genes in the Xq2.23 region and LDS. Our results may help to elucidate the lysosomal mechanisms in the pathogenesis of the disease and to better understand the expression of X-linked traits.