A Novel Homozygous Variant Associated With Distinct Clinical Phenotypes of SDR9C7 Nonsyndromic Epidermal Differentiation Disorder in Two Affected Patients From a Consanguineous Saudi Family

ABSTRACT

Background

Nonsyndromic Epidermal Differentiation Disorders (nEDD) are a group of heterogeneous disorders characterized by scaling and erythema. Pathogenic variants in SDR9C7 cause SDR9C7‐nEDD. We report two affected siblings from a consanguineous Saudi family presenting with distinct clinical phenotypes. The older affected brother exhibited generalized xerosis with both white and brown scaling, neck hyperpigmentation, and a velvety texture on the posterior neck. The younger sister showed diffuse xerosis with fine white scaling and marked palmoplantar hyperlinearity.

Methods

A family with two siblings suspected of a rare genetic disease was recruited. Given the phenotypic variability, whole‐exome sequencing (WES) was carried out for the proband brother to identify the genetic cause. Sanger sequencing was used to confirm the finding in the proband and to examine segregation analysis for the family members. In silico prediction tools were also used to assess the variant's pathogenicity.

Results

WES identified a novel homozygous SDR9C7 variant (NM_148897.3:c.154G>A; p.Val52Met). The affected sister was also homozygous for the variant. The variant was rare in global population databases, absent from the local database, and showed complete segregation within the family. Multiple prediction tools classified the variant as pathogenic and deleterious.

Conclusion

This study expands the clinical spectrum of SDR9C7‐nEDD, demonstrating its phenotypic variability even with the same novel variant. These findings highlight the contribution of additional modifying factors and emphasize the essential role of WES in diagnosing genetically heterogeneous skin disorders when genotype–phenotype correlation is uncertain.

Whole exome sequencing identified a novel homozygous SDR9C7 variant in two affected patients from a consanguineous Saudi family presenting distinct lamellar ichthyosis phenotypes.

1. Introduction

Nonsyndromic Epidermal Differentiation Disorders (nEDD) are a heterogeneous group of inherited skin disorders classified according to their causative gene (Akiyama et al. 2025). Short‐chain dehydrogenase/reductase family 9C member 7 (SDR9C7) nEDD (SDR9C7‐nEDD) is a rare subtype recently identified to be caused by variants in the SDR9C7 gene (Shigehara et al. 2016; Youssefian et al. 2021). Phenotypically, SDR9C7‐nEDD is characterized by abnormal skin scales all over the body, mild or localized erythema and hyperkeratosis (Akiyama et al. 2003; Oji et al. 2010). Additional notable features include palmoplantar hyperkeratosis, dyshidrosis, and in some patients, the presence of a collodion membrane at birth (Akiyama et al. 2003). Chronic superficial blistering and nail involvement, onychomycosis, may also occur (Akiyama et al. 2003).

The SDR9C7 gene, located at chr12q13.3, encodes a protein belonging to the short‐chain dehydrogenase and/or reductase enzyme superfamily. It comprises four exons and has 313 amino acid residues. SDR9C7 is mainly expressed in the granular and cornified epidermal layers (Shigehara et al. 2016). It has a role in vitamin A metabolism, where it transforms the trans‐retinal into trans‐retinol (Kowalik et al. 2009). Functional studies have shown that SDR9C7 is essential for keratinocyte differentiation and the skin barrier. Using a siRNA knockdown in HaCaT cells, Youssefian et al. (2021) showed a significant reduction in the SDR9C7 mRNA expression, accompanied by a thickened and disorganized epidermis with hyperkeratosis. Barrier integrity was also disrupted by the penetration of the hydrophilic fluorescent dye through the epidermis into the dermis (Youssefian et al. 2021). Therefore, downregulation alone is sufficient to disrupt the epidermal construct and epidermal barrier integrity, leading to ichthyosis‐like features.

Whole Exome Sequencing (WES) was performed to investigate the distinct phenotype observed in the two affected siblings from a consanguineous Saudi family. The analysis identified a novel missense variant in SDR9C7, associated with lamellar ichthyosis phenotype.

2. Material and Methods

2.1. IRB Approval

The study was approved by the Institutional Review Board at the College of Applied Medical Science, Taibah University (ID no. 2023/146/103 MLT). Written informed consent was obtained from the parents after explaining the study objective in Arabic. A family with two affected individuals suspected of a rare genetic disease was recruited for the study. The recruitment also included an unaffected sibling and parents. The clinical evaluation was performed by the responsible physicians at the King Fahad General Hospital, Madinah, Saudi Arabia.

2.2. DNA Extraction

Peripheral blood was withdrawn into an ethylenediaminetetraacetic acid tube from two affected siblings, an unaffected brother, and unaffected parents. The DNA was extracted based on the manufacturer's protocol using the QIAamp DNA mini kit (Qiagen cat. no. 51306).

2.3. Whole Exome Sequencing

WES was performed on the affected brother (Figure 1). The sequencing library was prepared using a SureSelect Human All Exon Kit V6 (Agilent, Santa Clara, CA), and the sequence reads were generated using HiSeq4000 (Illumina) with an average read depth of 100×. Adapters were automatically trimmed from pair‐sequence FASTQ reads before the analysis. The trimmed reads were then aligned to the human reference genome 38 (GRC38), followed by quality filtering and variant calling using commercially available algorithms. The VCF output file was further filtered and annotated using commercial software.

FIGURE 1.

The figure shows the clinical features of both affected siblings, the family pedigree, the Sanger sequence, and the evolution analysis. (A) The clinical features of both affected siblings. IV:2 Older brother from left to right; Lower legs and ankles showing xerosis with fine white and brown scaling; Palms demonstrating mild hyperlinearity without keratoderma; Posterior neck with velvety texture and fine white scaling. IV:3 Younger sister from left to right; lateral face and forehead with white and brown scaling; Palm with marked hyperlinearity; Axilla with fine white scaling and preserved texture. (B) The family pedigree shows the consanguinity in the family, the affected patient, and the carrier status. (C) The protein evolutionary alignment between species highlighted the Valine (Val) amino acid shown in Red. (D) The plotted sequence chromatograms show the variant position (highlighted in red dots) for the family members.

According to the family pedigree (Figure 1), an autosomal recessive mode of inheritance was suspected. Therefore, homozygous variants were prioritized. Variant nomenclature followed the HGVS recommendations, and classification was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines (Richards et al. 2015).

2.4. Sanger Sequencing and Prediction Tools

Sanger sequencing was performed following the standard protocol to validate the identified variant. A specific pair of primers targeting the region of interest was designed using the Primer 3 tool (http://primer3.ut.ee/ accessed 10 June 2025). This was used to confirm the variant in the affected brother, in affected sister, an unaffected sibling and the parents. The reference sequence of the gene of interest was downloaded from the Ensembl genome browser (https://m.ensembl.org/ accessed 20 June 2025). The resulting Sanger sequences were aligned to the reference using Clustal Omega (Madeira et al. 2024). The variant was evaluated using the combined annotation‐dependent depletion (CADD) score (GRCh38‐v1.7) (Rentzsch et al. 2018). It was further assessed using AlphaMissense and MutationTaster to estimate the potential effect on protein function (Cheng et al. 2023; Steinhaus et al. 2021). Variant novelty was checked in several databases, including gnomAD, ESP, and the 1000 Genomes Project (Auton et al. 2015; Chen et al. 2024; Tennessen et al. 2012), as well as ClinVar (https://www.ncbi.nlm.nih.gov/clinvar accessed on 25 June 2025) and the Human Genome Mutation Database (HGMD) (Auton et al. 2015).

3. Result

3.1. Clinical Features

The two siblings (male and female siblings) with a suspicion of congenital disorder of keratinisation were born to a consanguineous Saudi family (Figure 1). The older affected brother, who was 5 years old at the time of examination, showed generalized xerosis with both fine white and brown scaling involving the trunk and extremities, with sparing of the flexural areas. Clinical facial examination showed diffuse fine white scaling on the central cheeks, and brown adherent scales on the lateral cheeks. Fine white and brown scaling was observed on the lateral face and auricular areas. The posterior neck examination showed mild hyperpigmentation, a velvety texture, fine scaling, and mild accentuation of skin markings. The scalp showed fine white scales on the hair shaft in the frontal and temporal regions. The palms and soles showed mild hyperlinearity.

The younger affected sister, who was 2 years old at the time of examination, had generalized xerosis and fine white scaling largely over the trunk and extremities, with sparing of the flexural areas except for the axillae. Brown scaling, however, was not observed on the body. The key finding was found on the dorsal hands and palms. The dorsal hands were severely xerotic with significantly marked accentuation of the skin lines, and the palm showed marked hyperlinearity. Facial examination showed fine white scaling on the central cheeks and brown adherent crusts with faint hyperpigmentation on the lateral cheeks, especially in the preauricular area. White scaling was observed on the neck. The scalp appearance was the same as for the older brother. The axillary folds showed xerosis with fine white scaling.

Neither of the siblings had palmoplantar keratoderma, nail dystrophy, or a collodion membrane at birth. Developmental and growth milestones were normal, and no systemic abnormality was observed. There was no involvement of mucus membranes and no evidence of fungal, viral, or bacterial infections.

3.2. Genetic Testing Findings and Sanger Sequencing

WES revealed a novel homozygous missense variant in the SDR9C7 gene (NM_148897.3:c.154G>A; p.Val52Met). The variant results in the substitution of the valine, which is nonpolar with a hydrophobic side chain, by methionine, a nonpolar and sulfur‐containing amino acid with a thioether group, at amino acid position 52. This introduces a difference in size and potential reactivity. The CADD score for this variant is 26. The prediction tool AlphaMissense indicates this variant is pathogenic, supporting a maximum score of 0.92, and MutationTaster indicates it to be deleterious. A confirmation of this variant was performed using Sanger sequencing for the proband, which confirmed the homozygous state. The affected female was also found to carry the same homozygous variant. Additional Sanger sequencing of the parents and the unaffected brother revealed that they were heterozygous carriers for the variant. The variant is rarely found in the gnomAD database with a frequency of less than 0.01 (0.0000006) and is absent from the Exome Aggregation Consortium and the 1000 Genome Project (Auton et al. 2015; Chen et al. 2024; Tennessen et al. 2012). It is also not found in ClinVar and the HGMD (Auton et al. 2015), and it was not found in the local database out of 200 individuals. It is also found in highly conservative regions among different species (Figure 1). Additionally, the patient phenotype is highly consistent with SDR9C7‐nEDD presenting with a lamellar ichthyosis phenotype. The variant is evaluated as likely pathogenic based on the ACMG guidelines (Richards et al. 2015).

4. Discussion

SDR9C7‐nEDD is characterized by generalized scaling, mild or local erythema, and hyperkeratosis. Palmoplantar hyperlinearity, dyshidrosis, and, in some instances, a collodion membrane at birth, chronic superficial blistering, and onychomycosis are other significant manifestations. At least 17 unrelated families have been identified as having SDR9C7‐nEDD due to variants in SDR9C7 since it was first identified in Lebanese families (Shigehara et al. 2016). Herein, a novel missense variant in SDR9C7 was identified in two siblings of a consanguineous family with varied and distinct phenotypes of lamellar ichthyosis.

SDR9C7 variant (NM_148897.3:c.154G>A; p.Val52Met) was assessed following the ACMG guidelines for variant classification (Richards et al. 2015). The missense variant is absent from large population databases, which meets the PM2 (moderate evidence) criterion. In addition, co‐segregation analysis revealed that an unaffected sibling and parents carried the variant in the heterozygous state, adding to PP1 (moderate supporting evidence). In silico prediction tools all predicted a damaging effect on protein function (PP3, in support). Lastly, patient phenotypes are highly consistent with SDR9C7‐nEDD, supporting PP4 (supporting evidence). Overall, applying one moderate criterion (PM2) and three supporting criteria (PP1, PP3, and PP4) satisfies the threshold for the variant to be classified as likely pathogenic. Therefore, additional affected families and further functional analysis would be necessary to upgrade the classification.

Only 18 variants in SDR9C7 were reported to cause SDR9C7‐nEDD, including the current variant (Table S1) (frameshift or splice‐site), while the remaining were pathogenic or likely pathogenic missense variants that may also impair protein function through a loss of function mechanism. Notably, the current variant is located in exon 1, where several previously reported variants have been identified. As an example, a variant (NM_148897.2:c.214C>T; p.Arg72Trp) on the HEK293T cell line showed low expression on the protein level using Western blot (Shigehara et al. 2016). Additional analysis of the protein expression in skin fibroblasts for the same variant revealed a lower expression in the cornified layer compared to wild‐type (Shigehara et al. 2016). This exon encodes part of the highly conserved nicotinamide adenine dinucleotide and its phosphate‐binding domain, which has a cofactor‐binding function (Kowalik et al. 2009). Such disruption might lead to a defective skin barrier.

Several functional studies showed the role of the mutant SDR9C7 protein in the development of SDR9C7‐nEDD. Western blot analysis has revealed significantly decreased protein expression in the (NM_148897.3:c.599T>C; p.Ile200Thr) missense variant (Shigehara et al. 2016). This indicates instability of the resulting protein. Immunohistochemical analysis of lesional skin with the (NM_148897.3:c.826C>T; p.Arg276Cys) variant showed lower expression of SDR9C7 in the stratum corneum and stratum granulosum compared to the wild‐type (Takeichi et al. 2020). Histopathological examination of the skin biopsy from the same patient showed compact hyperkeratosis (Takeichi et al. 2020). This indicates potential defects in transcription or protein turnover of SDR9C7 in keratinocytes.

In addition, functional experiments in a mouse model confirmed the critical role of SDR9C7 in epidermal barrier formation. Knockdown of the sdr9c7 gene in mice resulted in defects of epidermal barrier formation, characterized by transepidermal water loss, dry skin, scaling, and hyperkeratosis (Youssefian et al. 2021). Knockout of sdr9c7 in mice showed loss of function of the mRNA (Takeichi et al. 2020). The sdr9c7 protein was not detected using immunohistochemistry. The heterozygous offspring were completely healthy and similar to the wild type (Takeichi et al. 2020). Another model example, a missense variant (NM_148897.3:c.454C>T; p.Arg152Trp) identified in the Chihuahua dog caused phenotypical defects similar to those observed in humans and showed similar findings to our cases (Kiener et al. 2023). These results suggest that a variant in the SDR9C7 gene is essential in maintaining the epidermal permeability barrier function.

Diverse phenotypes are a recognized phenomenon in genetically inherited skin diseases, in which the same variant exhibits considerable differences in clinical phenotypes in different patients as found in current finding. These differences could be caused by a modifier gene. This phenomenon was noticed in two different patients with lamellar ichthyosis and congenital ichthyosiform erythroderma, with the same variant (NM_000359.3:c.788G>A; p.Trp263X) in the transglutaminase‐1 (Ennouri et al. 2022). It was found that 40 missense polymorphisms in the filaggrin (FLG) gene were identified in the second patient compared to the first patient (Ennouri et al. 2022). In the current study, two siblings with the same variant in SDR9C7 exhibited diverse clinical phenotypes. A comparison table was generated to show the clinical variability (Table S2). Thirty‐one homozygous missense variants in the FLG were identified in the younger brother and were classified as benign based on ACMG guidelines. However, no genetic analysis was carried out for the younger sister, as WES was not carried out.

The care management was followed by the dermatologist. The patient's family was fully informed by the genetic consultant about the disease and its inheritance type. The family was informed about their probability of having another affected child. They were also recommended to follow up with the in vitro fertilization clinic for future pregnancies.

Consanguineous marriages are highly prevalent in Saudi Arabia, with an estimated prevalence of up to 65% (el‐Hazmi et al. 1995). Such a practice increases the probability of homozygosity for a rare and deleterious allele, resulting in a higher incidence of autosomal recessive diseases. Consanguinity also facilitates the recurrence and identification of rare or novel pathogenic variants that may remain undetected in genetically diverse populations. Indeed, studies conducted in multiple consanguineous Saudi families have identified several novel variants and previously unrecognized syndromes (Almalki et al. 2025; Alqahtani et al. 2023).

In conclusion, this study expands the mutational and clinical spectrum of SDR9C7‐nEDD by identifying a novel missense variant in two affected siblings from a consanguineous family. The molecular and clinical findings provide further evidence supporting the pathogenic role of SDR9C7 variants and emphasize the use of WES in identifying the rare variant in patients with distinct clinical phenotypes of SDR9C7‐nEDD, thereby facilitating accurate molecular diagnosis and genetic counseling.

Author Contributions

Faisal Almalki: writing – review and editing, visualization, validation, project administration, resources, supervision, writing – original draft, funding acquisition, investigation, conceptualization, methodology, formal analysis, software. Zaker Khoj: data curation, validation, visualization, writing – review and editing, writing – original draft. Essa Alharbi: investigation, methodology, validation, visualization, writing – review and editing, software. Osama Alsharif: supervision, writing – review and editing, writing – original draft, data curation, conceptualization.

Funding

This work was supported by Research, Development and Innovation Authority, Kingdom of Saudi Arabia, 12996‐iau‐2023‐TAU‐R‐3‐1‐HW.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Variants location on SDR9C7 and their types.

Table S2: Clinical differences between siblings.

Data Availability Statement

Data sharing is available upon request to the author.