Cardiac arrhythmia, developmental delay, epilepsy and ichthyosis due to Xp22.31 deletion: review of literature and case report

Introduction

Phenotypic heterogeneity in patients with identical molecular rearrangements, such as Xp22.31 deletion, is often underestimated and reduced to a single clinical feature—ichthyosis. Nevertheless, the clinical spectrum associated with this deletion can vary significantly, with some cases exhibiting additional or atypical manifestations that extend beyond the recognized phenotype. Such variability poses a diagnostic challenge for clinicians, particularly when interpreting whole genome sequencing (WGS) or chromosomal microarray analysis results.

A teenage boy observed in our institution, in addition to ichthyosis, presented with a paroxysmal form of atrial fibrillation-flutter, which necessitated the endocardial implantation of an electrical pacemaker at the age of 14 years old. For differential diagnosis, WGS was recommended and performed. It revealed an extensive deletion in the hemizygous state of a segment of the X chromosome with approximate coordinates chrX:g.6532778-8169874 (hg38) and a size of 1,637,097 base pairs (bp), including the entire STS gene.

After analyzing relevant literature, we established that, in addition to ichthyosis, carriers of the Xp22.31 deletion sometimes present with benign corneal opacification in approximately 10–50% of male cases (1), and cryptorchidism in 20% of men (2). Additionally, autism (3), intellectual disability (4,5), epilepsy (6), developmental delay (7), and renal abnormalities (8) have been described in male carriers of deletions of approximately 1.6 megabases (Mb). A recent study linked Xp22.31 deletions to an increased likelihood of atrial fibrillation/flutter in middle-aged individuals (9). Meanwhile, duplications of the same genomic region are considered to be benign structural variations (10).

In the present report, we describe three cases of the Xp22.31 deletion, with the case of one patient prompting us to conduct a retrospective analysis and search for similar deletions in the clinical records at the Veltischev Institute. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-87/rc).

Case presentation

We identified three male patients with X-linked ichthyosis (XLI), all of whom exhibited mild to moderate skin manifestations. Each proband was found to have hemizygous deletions in the Xp22.31 region, approximately 1.6 Mb in size, involving seven genes: VCX3A, STS, MIR651, MIR4767, VCX, PUDP, PNPLA4 in Patients 2 and 3, and an additional gene, VCX2, in Patient 1 (Figure 1).

Figure 1 A schematic representation of the Xp22.31 region of the X chromosome (hg38), indicating the locations of various genes and CpG islands. The deleted regions in three probands (P1, P2, and P3) diagnosed with X-linked ichthyosis are depicted. In all patients, the deletion affects the genes VCX3A, STS, MIR651, MIR4767, VCX, PUDP, and PNPLA4. In P1, the deletion additionally includes the VCX2 gene. P, proband.

Among the affected genes, only the STS has well-established clinical significance, with deletions and pathogenic variants of this gene being strongly associated with XLI.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patients’ parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Case 1 (P1)

Proband T.A., a 16-year-old male, was referred to the pediatric cardiology department of the Veltischev Institute with cardiac rhythm abnormalities. He was born at full term to unrelated parents following a healthy fourth pregnancy (pregnancies 1–3 resulted in medical abortions). His birth weight was 2,900 g, and his length was 50 cm. He required medical attention after birth due to severe muscle hypotonia and was breastfed until 9 months of age. The proband’s early motor development was typical—he began supporting his head at 2 months and walking at 12 months. Phrasal speech began at 3 years of age. In addition to cardiac arrhythmia, the proband presented with testicular microlithiasis, ichthyosis (characterized by ‘plate-like’ desquamation), and Gilbert’s syndrome, as well as phenotypical features including epicanthus, microgenia, and diastema. His family history does not contain relevant data (Figure 2).

Figure 2 The pedigrees of three families (P1, P2, P3). The probands (P1, P2, and P3) are marked with arrows and diagnosed with X-linked ichthyosis (filled squares). Additional annotations include intrauterine fetal death, ectopic pregnancies, and previous marriages, reflecting the detailed family histories of the patients. P, proband.

Sinus bradycardia was first documented at the age of 5 years, following an episode of bronchitis. An electrocardiogram (ECG) performed at the age of 7 revealed persistent sinus bradycardia, with heart rates of 52–54 bpm while lying, 56–58 bpm while standing, and 65–115 bpm during exertion. Holter monitoring recorded heart rates of 66, 53, and 60 bpm, with a minimum of 41 bpm and a maximum of 135 bpm, and episodes of atrial rhythm during the night. Echocardiography (Echo-CG) showed normal atrial and ventricular sizes, as well as a normal ejection fraction (EF). At the age of 8, an ECG confirmed atrial rhythm with a heart rate of 47–67 bpm, while post-exercise testing showed a normal sinus rhythm with a heart rate of 88 bpm. Holter monitoring revealed severe bradycardia and rhythm pauses up to 1,654 ms in length.

At the age of 14, the patient experienced syncope without any prior premorbid history. ECG conducted immediately post-syncope showed atrial rhythm and bradycardia, with subsequent restoration of sinus rhythm upon standing. Holter monitoring at that time indicated severe bradycardia, rhythm pauses up to 3,436 ms, and polymorphic ventricular extrasystole. Echo-CG demonstrated slight dilation of the left ventricular cavity, with a mild narrowing of the inflow tract at the basal level and an expanded outflow tract, particularly at the apex.

At age of 15 years, the patient experienced marked sinus bradycardia and a shortening of the QTc interval to 335 ms. Holter monitoring revealed pronounced bradycardia, frequent asystole lasting more than 4 seconds, and polymorphic ventricular extrasystole. Echo-CG showed similar structural abnormalities to those observed in the previous year. A tilt test, inducing syncope with generalized tonic seizures and short asystolic episodes (2,543 and 12,516 ms), was performed, followed by restoration of sinus rhythm. The tilt test result was positive, confirming the diagnosis of cardioinhibitory variant (with asystole) of reflex (vasovagal) syncope (VASIS 2) (11).

Considering the proband’s history of syncope without a reflex component, progressive bradycardia, increase frequency and duration of asystole episodes over a long observation period (since the age of 7), signs of myocardial electrical instability (QTc interval shortening and polymorphic ventricular arrhythmia up to 9%), and arrhythmogenic myocardial dysfunction (IIA class of indications), endocardial implantation of an electrical pacemaker was deemed necessary. A Boston Scientific Essentio MRI SR pacemaker (model 821267, RZN 139) was implanted when the patient was 15 years old.

To determine the potential genetic basis for the cardiac rhythm abnormalities, the patient underwent WGS at age 16. WGS revealed a hemizygous deletion of approximately 1.6 Mb on the X chromosome (chrX:g.6532778-8169874), which included the entire STS gene (OMIM: 300747). This deletion is known to be pathogenic and is associated with XLI (steroid sulfatase deficiency), as documented in the ClinVar and Decipher databases.

Case 2 (P2)

Proband S., a 3-year-old male, was referred to a neurologist due to developmental delay, increased appetite, and seizures. He was born at full term (41.3 weeks gestation) via cesarean section to unrelated parents, following a complicated second pregnancy (previous pregnancy ended in medical abortion, and the subsequent one resulted in the birth of a healthy girl). The pregnancy was complicated by a threatened miscarriage. At birth, his weight was 3,680 g, length 53 cm, and head circumference 35 cm, with an Apgar score of 7/8. Early developmental delays were evident; he began supporting his head at 4 months, sitting at 8 months, and walking with support at 1.5 years. Delays in speech and psychological development were also observed.

His family history is unremarkable (Figure 2). In the first year of life, he experienced seizures, which were managed with Depakine, resulting in a positive response. At age 3, an electroencephalogram (EEG) conducted during antiepileptic treatment revealed isolated epileptiform activity in the right frontotemporal region. A brain CT scan showed no structural abnormalities, while an abdominal ultrasound revealed hepatomegaly, reactive pancreatic changes, and an accessory spleen lobe. In addition to epilepsy and developmental delay, S. exhibited features of autism spectrum disorder, and clinical suspicion of Prader-Willi syndrome was raised, based on obesity, ametropia, and exotropia.

Upon examination, the patient demonstrated skin manifestations of ‘plate-like’ desquamation, a round face, fleshy auricles, a hydrocephalic skull, frontal tubercles, a saddle-shaped dorsum of the nose, an upturned nasal tip, a long philtrum, epicanthus, strabismus, a short neck, obesity, and syndactyly of the 2nd and 3rd toes.

To investigate the genetic cause of these clinical features, the proband underwent trio WGS, which identified a microdeletion of the short (p) arm of the X chromosome, spanning from 6634671 to 8129471 (hg38), covering the Xp22.31 region, with a total size of 1,494,801 bp. Pathogenic structural variants within this region are associated with XLI, intellectual disability, and epilepsy. Similar variants with comparable phenotypes have been registered in the Decipher database (Decipher Sample IDs: 385657, 338884, 322081, 412741) and classified as pathogenic or probably pathogenic. Notably, similar structural variants are absent in the gnomAD SVs v4.1.0 population frequency database.

This deletion was present in the proband’s mother, who reports dry skin but does not exhibit any neurological or developmental symptoms, but not in the father. The rearrangement was further confirmed by chromosomal microarray analysis, with the result: arr(GRCh38) Xp22.31(66346718129471)x0.

Case 3 (P3)

Proband M., a 2-year-5-month-old male, was referred to a geneticist due to developmental delay and skin abnormalities. He was born at term (41.3 weeks gestation) via cesarean section to unrelated parents, following a third pregnancy (the first pregnancy resulted in a healthy girl, the proband’s half-sibling, and the second pregnancy was ectopic). The pregnancy was achieved through in vitro fertilization and was complicated by a threatened miscarriage at 16 and 20 weeks of gestation. At birth, the patient weighed 3,000 g, measured 50 cm in length, and had a normal head circumference, with an Apgar score of 8/9. Early motor development was delayed, with M. beginning to support his head at 1.5–2 months, sitting at 8 months, and walking at 12 months. His physical development was delayed from 1.5 years onward, and at the time of observation, phrasal speech had not developed.

At 1 year of age, abdominal ultrasound revealed splenomegaly and lymphadenopathy at the root of the mesentery. Follow-up imaging at 1.5 years showed persistent splenomegaly and hepatomegaly. Three months after initial lymphadenopathy was noted, reactive changes were observed in the patient’s blood work. The patient exhibited muscular dystonia with adductor spasms, ichthyosis, atopic dermatitis, and delays in both physical and cognitive development. Additionally, he demonstrated mild hypermetropia with hypermetropic astigmatism, epicanthus, microgenia, and diastema. M. communicated using single words, syllables, and gestures and could follow basic instructions, though he had difficulty concentrating.

An ECG at the time of observation showed supraventricular pacemaker migration, mild bradycardia, and significant arrhythmia with a heart rate ranging from 76–118 bpm. Abnormal conduction along the right bundle branch was noted, along with disturbances in repolarization in the posterior wall of the left ventricle (decreased z.T HI.aVF). The QT interval shortened to 326 ms during bradycardia (normal >350 ms). Holter monitoring recorded 129,490 QRS complexes over 23 hours, with 1,094 artifacts, primarily between 05:00 and 06:00 hours. The predominant rhythm was sinus, with a tendency for bradycardia at night. The average heart rate was 98 bpm, the maximum heart rate was 150 bpm while walking, and the minimum heart rate was 72 bpm during sleep. Echocardiogram revealed ectopic chordae, mitral valve chordae dysfunction, and increased trabecularity of the left ventricle.

Further abdominal ultrasound showed persistent splenomegaly and diffuse pancreatic changes. EEG revealed disorganized cortical rhythm at 7 Hz, with moderate dysfunction of the diencephalic brain structures but no focal changes or epileptiform activity.

Genetic testing via chromosomal microarray analysis identified a deletion in the Xp22.31 region and two additional structural rearrangements: arr(GRCh38): Xp22.31(6540898–8167603)x0, 5p12p11(45520382–46389237)x3, and 6q27(169246506-169252602)x1. The proband’s parents have not been tested for these structural rearrangements.

Discussion

Currently, according to the American College of Medical Genetics and Genomics (ACMG) guidelines, the Xp22.31 deletion is classified as pathogenic and leads to ichthyosis. XLI, the second most common form of ichthyosis, affects approximately 1 in 6,000 to 1 in 2,000 males and typically appears early in life, regardless of ethnicity or geography. While it predominantly impacts males due to its X-linked recessive inheritance, female carriers may show mild symptoms like dry skin (12).

The human Xp22.31 region is known to be highly unstable, with frequent genomic rearrangements (13). A typical Xp22.31 deletion is approximately 1.6 Mb in size and includes the VCX3A, PUDP, STS, VCX, PNPLA4 and VCX2 genes, as well as the miRNAs MIR4767 and MIR651. The loss of one or more of these genes may contribute to the phenotypic diversity observed in affected individuals. Additionally, there are two CpG sites in this region (Figure 1). Therefore, Xp22.31 microdeletions should be discussed in the context of the syndrome of adjacent genes, with the resulting phenotype depending on the genes included in them (14). Duplications of Xp22.31 involving the STS gene are generally relatively benign but may moderately increase the risk of certain phenotypes and reduce the severity of depressive symptoms. Male carriers more frequently present with inguinal hernia and bipolar disorder, while female carriers show higher rates of reflux and skin disorders (15).

Among pediatric male patients with cardiac arrhythmias and Xp22.31 deletion, tachycardia is recorded in 53% of cases, bradycardia in 40%, and atrial fibrillation (AF) in 20%, with stress and febrility identified as primary triggers for arrhythmic events (9). The attack of arrhythmia resolves in 55% of them within 1 hour, and in 86% breathing exercises successfully help cope with it. In our cohort, patients P1 and P3 presented with bradycardia. Wren et al. found no direct association between the severity of cardiac symptoms and the degree of ichthyosis, nor was there any correlation between arrhythmias and intellectual development or genital abnormalities. Among patients with Xp22.31 deletion, those with arrhythmias were 3.2 times more likely to have anemia, 4.9 times more likely to have bowel problems, and 2.9 times more likely to have asthma (9). PNPLA4, VCX3A, VCX and VCX2 have been associated with gastrointestinal health in males with Xp22.31 deletion, though causality has not been established. An association between asthma and PNPLA4 was observed only in females.

STS is involved in the regulation of fibrosis signaling pathways, presumably through Ccn2(Ctgf) (16-18), and avoids lyonization, leading to its expression in women activating myofibroblasts via RhoA/ROCK signaling to a greater extent than in men. This sex-dependent difference is reflected in the lower calcification of the aortic valve and a better prognosis for aortic stenosis diagnosis in women (19). Since aortic stenosis is one of the causes of AF, STS deficiency may indirectly contribute to arrhythmogenesis. In turn, a recent review proposed that inhibition of STS in rodent models enhances acetylcholine release in the central nervous system, potentially affecting heart rate regulation and increasing the likelihood of AF (20,21). Furthermore, men with STS deletions exhibit a reduction in serum testosterone levels both before and after puberty (22), however, in the context of AF, attention has been drawn to the role of dehydroepiandrosterone sulfate (DEAS), where lower blood concentrations are associated with a reduced risk of AF development (23). In boys with STS deficiency, DEAS levels are elevated before puberty and decrease post-puberty, although not significantly, which may indirectly contribute to AF pathogenesis.

Research using rodent models has demonstrated that STS is actively expressed in the adult brain, suggesting its importance in neurodevelopment and ongoing brain function via multiple mechanisms, both direct and indirect, such as alterations in the expression of the Ccn2 (Ctgf), Ccn3(Nov) and miR-133a (16,24). Thus, adult male mice with STS deletion exhibit attention deficits compared to wild-type controls, with preserved or even enhanced motor responses regulation (25). Additionally, these mice display signs of hyperactivity, increased anxiety, levels of aggression, and assertive behavior (26). In humans, a study involving 82 males with confirmed XLI showed that both adults and children with this condition scored significantly higher than population norms on measures of inattention, impulsivity, autism-related traits, and psychological distress. Notably, half of the children with XLI had been diagnosed with a developmental disorder, including ADHD, autism, and speech delay (27).

The PNPLA4 encodes calcium-independent phospholipase A2η (iPLA2η), which functions as an acylglycerol and retinol transacylase as well as a triglyceride hydrolase. The nonsense mutation c.559C>T:p.R187X in PNPLA4 has been identified as the cause of mitochondrial respiratory chain complex IV deficiency in a 10-year-old boy (28). Culturing his fibroblasts in a low-glucose medium revealed deficiencies in complexes I and III of the respiratory chain, but lentiviral-mediated expression of exogenous PNPLA4-V5 restored enzymatic activity in complexes III and IV. Similarly, a male patient (Pt133) with an Xp22.31 deletion exhibited a relatively severe deficiency of respiratory chain complex I from birth. Nevertheless, this variant was identified in 23 males according to the gnomAD v4.1.0 population frequency database.

It has been proposed that deletion of the PUDP and PNPLA4 genes could contribute to intellectual disability, due to the high levels of these transcripts in the human brain (29).

VCX proteins are expressed in human neurons, as evidenced by immunohistochemical postmortem analysis of the hippocampus and cerebral cortex (30). VCX-A specifically binds to the 5′ end of capped mRNAs, thereby preventing their degradation. The exogenous expression of VCX-A in primary rat hippocampal neurons has been shown to promote neurite branching, while its absence is associated with intellectual disability.

The roles of the MIR651, MIR4767 genes remain unclear in relation to the development of disorders observed in patients with Xp22.31 deletions. However, miR-4767, in conjunction with miR-4707-5p, enhances apoptosis by targeting the 3′UTR of two apoptosis inhibitors, API5 and BCL2L12, respectively (31). It was shown that miR651 is positively correlated with serum protein levels of IP10 and MCP-1, markers commonly elevated in patients with hepatocellular carcinoma (32). There is evidence that miR651 modulates the expression of genes related to immune response-related pathways, including B- and T-cell receptor signaling, and interacts with the key tumor suppressor protein p53, which may contribute to tumorigenesis.

Patient 3 harbored additional genetic variants. The duplication 5p12p11(4552038246389237)x3, encompassing exons 1–2 of the HCN1 gene, partially overlaps (71%) with the variant gssvG29593, reported in the DGV Gold database with a frequency of 0.04% (5 out of 12,500 individuals). No full (≥80%) reciprocal overlaps with known structural variants in the gnomAD entries were found, indicating that this variant is rare in the general population. However, this duplication partially overlaps with a CNV reported in patient 261759 from the Decipher database, a 6-year and 1-month-old female with a duplication chr5:45391438–46144837 affecting exons 1-4 of HCN1. Her clinical presentation included seizures and specific learning disability, with no other clinically significant CNVs identified. The duplication was inherited from her father, who had a history of dyslexia, suggesting a potential hereditary predisposition to neurodevelopmental traits. It is important to note that the disorders associated with HCN1, such as Developmental and epileptic encephalopathy 24 (OMIM: 615871) and Generalized epilepsy with febrile seizures plus, type 10 (OMIM: 618482), are linked to dominant-negative missense variants exhibiting gain-of-function effects (33,34). Furthermore, patient P3 did not present with epileptic seizures, which significantly reduces the likelihood that this duplication is of clinical significance.

Another variant, 6q27(169246506–169252602)x1, affects exons 2 and 3 of the THBS2 gene, which exhibits a very high probability of loss-of-function intolerance (pLI = 0.9986, according to gnomAD). In gnomAD CNVs v4.1.0, only 5 individuals among 464,297 (0.00108%) were reported to carry a full gene deletion of THBS2. Mouse models with complete Thbs2 knockout (Thbs2^−/−) are viable and fertile but exhibit several tissue-specific abnormalities, including skin fragility, increased tail flexibility, disorganized collagen fibers, and increased vascular density, potentially due to impaired fibrillogenesis and altered adhesive properties of mesenchymal cells (35). In addition, a heterozygous missense variant, NM_003247.5:c.2686T>C (p.Cys896Arg), in THBS2 has recently been reported as causative for Ehlers-Danlos syndrome, further supporting the functional importance of this gene in connective tissue biology (36). However, from a clinical standpoint, the phenotypic consequences of losing a single copy of the gene remain uncertain, as no heterozygous large deletions or confirmed loss-of-function variants have been reported in association with a defined clinical phenotype.

The clinical presentation of the patients described in this report (Table 1) is generally consistent with previously published phenotypic features associated with Xp22.31 deletion (37). Despite numerous attempts to establish a correlation between the size of chromosomal deletions and the severity of the phenotype, it is often referred to as a adjacent gene syndrome (14). However, we found no molecular mechanisms in the literature explaining the phenotypic variability based solely on this theory. We hypothesize that the position effect could offer an explanation, suggesting that genes located adjacent to the Xp22.31 deletion, such as NLGN4X and ANOS1, may undergo altered expression due to changes in the local chromatin structure or the creation of new interactions with regulatory elements like enhancers or silencers. This hypothesis could account for the absence of intellectual disability in P1, whose Xp22.31 deletion is located further from NLGN4X compared to P2 and P3 (Figure 1). NLGN4X is associated with Intellectual developmental disorder, X-linked and {Autism susceptibility, X-linked 2} (OMIM: 300495).

In this report, we have not addressed the potential impact of CpG sites on the phenotype, as their deletion appears not to contribute significantly to genotype-phenotype variation in males.

Conclusions

Our report emphasizes the critical need for comprehensive neurological and cardiac evaluations in patients with Xp22.31 deletions. We propose that laboratories reporting such deletions should incorporate assessments of neurological, cardiac, and other relevant clinical features in their interpretation, alongside the recognition of skin manifestations. In conclusion, we aim to alert neurologists, cardiologists, dermatologists, and geneticists (both clinical and laboratory) to the broader clinical spectrum associated with Xp22.31 deletions that we have described.

Our results expand upon knowledge about the spectrum of genotypes and phenotypes of the Xp22.31 deletion, which may be valuable in medical genetic counseling and prenatal diagnostics.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-87/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-87/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-87/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patients’ parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Hung C, Ayabe RI, Wang C, et al. Pre-Descemet corneal dystrophy and X-linked ichthyosis associated with deletion of Xp22.31 containing the STS gene. Cornea 2013;32:1283-7. [Crossref] [PubMed]
2. Brcic L, Underwood JF, Kendall KM, et al. Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank. J Med Genet 2020;57:692-8. [Crossref] [PubMed]
3. Baek WS, Aypar U. Neurological Manifestations of X-Linked Ichthyosis: Case Report and Review of the Literature. Case Rep Genet 2017;2017:9086408. [Crossref] [PubMed]
4. Addis L, Rosch RE, Valentin A, et al. Analysis of rare copy number variation in absence epilepsies. Neurol Genet 2016;2:e56. [Crossref] [PubMed]
5. Addis L, Sproviero W, Thomas SV, et al. Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses. J Med Genet 2018;55:607-16. [Crossref] [PubMed]
6. Wu Y, Wu D, Lan Y, et al. Case report: Sex-specific characteristics of epilepsy phenotypes associated with Xp22.31 deletion: a case report and review. Front Genet 2023;14:1025390. [Crossref] [PubMed]
7. Ben Khelifa H, Soyah N, Ben-Abdallah-Bouhjar I, et al. Xp22.3 interstitial deletion: a recognizable chromosomal abnormality encompassing VCX3A and STS genes in a patient with X-linked ichthyosis and mental retardation. Gene 2013;527:578-83. [Crossref] [PubMed]
8. Schierz IAM, Giuffrè M, Cimador M, et al. Hypertrophic pyloric stenosis masked by kidney failure in a male infant with a contiguous gene deletion syndrome at Xp22.31 involving the steroid sulfatase gene: case report. Ital J Pediatr 2022;48:19. [Crossref] [PubMed]
9. Wren G, Baker E, Underwood J, et al. Characterising heart rhythm abnormalities associated with Xp22.31 deletion. J Med Genet 2023;60:636-43. [Crossref] [PubMed]
10. Hu H, Huang Y, Hou R, et al. Xp22.31 copy number variations in 87 fetuses: refined genotype-phenotype correlations by prenatal and postnatal follow-up. BMC Med Genomics 2023;16:69. [Crossref] [PubMed]
11. Brignole M, Menozzi C, Del Rosso A, et al. New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification. Analysis of the pre-syncopal phase of the tilt test without and with nitroglycerin challenge. Vasovagal Syncope International Study. Europace 2000;2:66-76. [Crossref] [PubMed]
12. Zhou B, Liang C, Li P, et al. Revisiting X-linked congenital ichthyosis. Int J Dermatol 2025;64:51-61. [Crossref] [PubMed]
13. Liu P, Erez A, Nagamani SC, et al. Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications. Hum Mol Genet 2011;20:1975-88. [Crossref] [PubMed]
14. van Steensel MA, Vreeburg M, Engelen J, et al. Contiguous gene syndrome due to a maternally inherited 8.41 Mb distal deletion of chromosome band Xp22.3 in a boy with short stature, ichthyosis, epilepsy, mental retardation, cerebral cortical heterotopias and Dandy-Walker malformation. Am J Med Genet A 2008;146A:2944-9. [Crossref] [PubMed]
15. Gubb SJA, Brcic L, Underwood JFG, et al. Medical and neurobehavioural phenotypes in male and female carriers of Xp22.31 duplications in the UK Biobank. Hum Mol Genet 2020;29:2872-81. [Crossref] [PubMed]
16. Humby T, Cross ES, Messer L, et al. A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis. Psychoneuroendocrinology 2016;74:363-70. [Crossref] [PubMed]
17. Brcic L, Wren GH, Underwood JFG, et al. Comorbid Medical Issues in X-Linked Ichthyosis. JID Innov 2022;2:100109. [Crossref] [PubMed]
18. Rebolledo DL, Lipson KE, Brandan E. Driving fibrosis in neuromuscular diseases: Role and regulation of Connective tissue growth factor (CCN2/CTGF). Matrix Biol Plus 2021;11:100059. [Crossref] [PubMed]
19. Aguado BA, Walker CJ, Grim JC, et al. Genes That Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts. Circulation 2022;145:513-30. [Crossref] [PubMed]
20. Rhodes ME, Li PK, Burke AM, et al. Enhanced plasma DHEAS, brain acetylcholine and memory mediated by steroid sulfatase inhibition. Brain Res 1997;773:28-32. [Crossref] [PubMed]
21. Wren G, Davies W. Sex-linked genetic mechanisms and atrial fibrillation risk. Eur J Med Genet 2022;65:104459. [Crossref] [PubMed]
22. Idkowiak J, Taylor AE, Subtil S, et al. Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty. J Clin Endocrinol Metab 2016;101:2545-53. [Crossref] [PubMed]
23. Krijthe BP, de Jong FH, Hofman A, et al. Dehydroepiandrosterone sulfate levels and risk of atrial fibrillation: the Rotterdam Study. Eur J Prev Cardiol 2014;21:291-8. [Crossref] [PubMed]
24. Humby T, Davies W. Brain Gene Expression in a Novel Mouse Model of Postpartum Mood Disorder. Transl Neurosci 2019;10:168-74. [Crossref] [PubMed]
25. Davies W, Humby T, Trent S, et al. Genetic and pharmacological modulation of the steroid sulfatase axis improves response control; comparison with drugs used in ADHD. Neuropsychopharmacology 2014;39:2622-32. [Crossref] [PubMed]
26. Trent S, Dean R, Veit B, et al. Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder. Psychoneuroendocrinology 2013;38:1370-80. [Crossref] [PubMed]
27. Chatterjee S, Humby T, Davies W. Behavioural and Psychiatric Phenotypes in Men and Boys with X-Linked Ichthyosis: Evidence from a Worldwide Online Survey. PLoS One 2016;11:e0164417. [Crossref] [PubMed]
28. Kohda M, Tokuzawa Y, Kishita Y, et al. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet 2016;12:e1005679. [Crossref] [PubMed]
29. Labonne JDJ, Driessen TM, Harris ME, et al. Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31. J Clin Med 2020;9:274. [Crossref] [PubMed]
30. Jiao X, Chen H, Chen J, et al. Modulation of neuritogenesis by a protein implicated in X-linked mental retardation. J Neurosci 2009;29:12419-27. [Crossref] [PubMed]
31. Lu W, Huang SY, Su L, et al. Long Noncoding RNA LOC100129973 Suppresses Apoptosis by Targeting miR-4707-5p and miR-4767 in Vascular Endothelial Cells. Sci Rep 2016;6:21620. [Crossref] [PubMed]
32. Damjanovska S, Alao H, Zebrowski E, et al. During HCV DAA Therapy Plasma Mip1B, IP10, and miRNA Profile Are Distinctly Associated with Subsequent Diagnosis of Hepatocellular Carcinoma: A Pilot Study. Biology (Basel) 2022;11:1262. [Crossref] [PubMed]
33. Nava C, Dalle C, Rastetter A, et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet 2014;46:640-5. [Crossref] [PubMed]
34. Marini C, Porro A, Rastetter A, et al. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain 2018;141:3160-78. [Crossref] [PubMed]
35. Kyriakides TR, Zhu YH, Smith LT, et al. Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis. J Cell Biol 1998;140:419-30. [Crossref] [PubMed]
36. Hadar N, Porgador O, Cohen I, et al. Heterozygous THBS2 pathogenic variant causes Ehlers-Danlos syndrome with prominent vascular features in humans and mice. Eur J Hum Genet 2024;32:550-7. [Crossref] [PubMed]
37. Gunasekaran P, Saini L, Rajial T, et al. Chromosome Xp22.3 deletion syndrome with X-linked ichthyosis, Kallmann syndrome, short stature, generalized epilepsy, hearing loss, attention deficit hyperactivity disorder, and intellectual disability – A rare report with review of literature. J Neurosci Rural Pract 2024;15:425-30.