Schwartz–Jampel Syndrome Type 1 in a Balouch Patient: A Novel Compound Heterozygous HSPG2 Variant Revealed by Whole-Exome Sequencing

The heparan sulfate proteoglycan 2 (HSPG2) gene, an evolutionarily conserved locus located on chromosome 1p36.1-p35, spans approximately 120 kb. It encodes the large core protein (perlecan) of approximately 467 kDa consisting of 4391 amino acids (1, 2). Structurally, perlecan includes glycosaminoglycan chains attached at its N-terminal end and is organized into five distinct functional domains (I-V) (2, 3). Perlecan, a secreted proteoglycan found within the matrix of various tissues such as cartilage, bone marrow, and skeletal muscle, participates in diverse biological processes, including growth factor binding, angiogenesis, cell adhesion, and maintenance of basement membranes and cartilage (2, 4-6).

Pathogenic variants in the HSPG2 gene are associated with two categories of skeletal disorders: Dyssegmental dysplasia, Silverman-Handmaker type (DDSH; OMIM #224410) and Schwartz-Jampel syndrome type 1 (SJS1; OMIM #255800) (2). The DDSH, a lethal condition in the neonatal period, arises from functional null mutations in the HSPG2 gene, leading to a disturbance in the perlecan secretion into the extracellular matrix. Affected individuals exhibit profound skeletal defects, bowed limbs, short stature, encephalocele, and flattened facial and vertebral malformations (7).

Schwartz–Jampel syndrome type 1 (or chondrodystrophic myotonia) represents a rare genetic disorder with an autosomal recessive (AR) inheritance pattern. This condition is characterized by the presence of skeletal dysplasia and myotonic myopathy, often presenting with a range of phenotypic manifestations such as joint contractures, pigeon breast, reduced stature, and abnormal ear morphology (8, 9). Disease severity correlates with mutation location and residual protein function (2). The SJS1 is classified into two subgroups: SJS1A represents a less severe phenotype, which usually has mutations associated with this phenotype located near the C-terminal region within domains IV and V, and SJS1B (severe manifestation with neonatal onset) (2, 10). Consequently, the diagnosis of SJS1 relies on clinical findings, subsequently requiring molecular validation. The therapeutic intervention of this condition is primarily supportive, focusing on alleviating myotonia (9).

In this case report, we describe an Iranian patient with a novel pathogenic variant in the HSPG2 gene (NM_005529.7: c.1928G>A; p.Arg643His, c.4378G>T; p.Glu1460Ter) identified through whole-exome sequencing (WES) and consistent with SJS1. This finding extends the mutational spectrum and advances our knowledge of genotype-phenotype correlation in HSPG2-related disorders. Unlike previously reported mutations, this compound heterozygous variant includes a novel missense mutation and a nonsense mutation. This offers new insight into SJS1 heterogeneity and highlights the importance of expanding the variant database.

The SJS1 is a rare AR disorder caused by pathogenic mutations in HSPG2, the gene encoding perlecan (7). This protein plays a multifaceted role in biological processes such as mediating growth factor interactions, angiogenesis, cell adhesion, and maintenance of basement membranes and cartilage (2, 6). Therefore, pathogenic variants in this gene that compromise the synthesis or secretion of perlecan can cause multisystem disorders such as SJS1 and DDSH (7). The clinical hallmarks of SJS1 include myotonia, chondrodysplasia, joint contractures, and craniofacial dysmorphism (8).

So far, over forty distinct HSPG2 variants have been published in SJS1 patients (11). According to the documented variant mapping, the majority of these variants are located in domain IV, followed by domains III, II, V, and I, respectively (9). Since these domains mediate various biological functions, such as growth factor binding (domain I), stabilizing basement membranes (domain III), and interacting with extracellular ligands (domain IV), changes in different domains may result in different clinical outcomes (2).

Clinical data from reported cases showed myotonic symptoms in all patients, along with typical facial features due to skeletal dysplasia (9). In 2013, Bauche et al. described the first case with a compound heterozygous mutation involving domains I and III. This patient experienced spontaneous improvement in muscle symptoms (12). After that, Brugnoni et al. reported the second case of spontaneous improvement in muscle signs, with mutations located in domains III and V (9). Our patient has compound heterozygous variants located in domain III of the perlecan protein (Figure 1). Despite the similarity in domain involvement with previously reported cases, our patient did not show any spontaneous improvement in symptoms. This difference may reflect the particular nature of his variants. The truncating mutation could eliminate important downstream domains, while the missense substitution may lead to local misfolding or protein instability. The instability could prevent functional compensation that might otherwise occur. This finding may indicate that the identified variants have a more destructive impact on functional performance or that specific amino acid substitutions and truncations lead to protein misfolding or degradation.

Figure 1.

Localization of the amino acid change positions of identified variants in this report on a schematic representation of perlecan

One of the identified variants in our patient (c.4378G>T) results in a premature stop codon, which causes the early truncation of the protein and loss of the following domains. Another variant is a missense mutation (c.1928G>A) with a very low allele frequency in the Iranome database. It is specifically absent in the homozygous state and present at a heterozygous frequency of 0.0198 among 202 healthy individuals from the Balouch ethnic group, which matches the patient's ethnicity. Only two individuals in this population were heterozygous carriers, supporting the rare nature of the variant and its potential pathogenicity. Additionally, multiple prediction tools supported the deleterious effect of these variants: SIFT predicted this variant as “deleterious”, PolyPhen rated it as “probably damaging”, and MutationTaster marked this variant as disease-causing. These tools combine evolutionary conservation, biochemical properties, and known variant databases to determine functional impact. However, careful interpretation is needed along with clinical and population data. The coexistence of this missense variant with a second pathogenic truncating variant in a compound heterozygous state likely explains the disease phenotype in our patient.