Emergence of lingual dystonia and strabismus in early-onset SCN8A self-limiting familial infantile epilepsy.

Pathogenic variants in SCN8A are associated with a broad phenotypic spectrum, including Self-Limiting Familial Infantile Epilepsy (SeLFIE), characterized by infancy-onset age-related seizures with normal development and cognition. Movement disorders, particularly paroxysmal kinesigenic dyskinesia typically arising after puberty, may represent another core symptom. We present the case of a 1-year-old girl with a familial disposition to self-limiting focal seizures from the maternal side and early-onset orofacial movement disorders associated with SCN8A-SeLFIE. Brain MRI was normal. Genetic testing revealed a maternally inherited SCN8A variant [c.4447G > A; p.(Glu1483Lys)]. After the introduction of valproic acid, she promptly achieved seizure control as well as complete remission of strabismus and a significant decrease in episodes of tongue deviation. Family history, genetic findings, and epilepsy phenotype are consistent with SCN8A-SeLFIE. Movement disorders are an important part of the SCN8A phenotypic spectrum, and this case highlights the novel early-onset orofacial movement disorders associated with this condition. The episodes of tongue deviation and protrusion suggest focal oromandibular (lingual) dystonia. Additionally, while infantile strabismus or esophoria is a common finding in healthy individuals, our case raises the possibility of an ictal origin of the strabismus. This study underscores the importance of recognizing and addressing movement disorders in SCN8A-SeLFIE patients, particularly the rare early-onset orofacial manifestations. It adds to the growing body of knowledge regarding the diverse clinical presentations of SCN8A-associated disorders and suggests potential avenues for clinical management and further research.

Crouzon syndrome complicated with binocular strabismus and extraocular muscle fibrosis: a case report.

BACKGROUND: Crouzon syndrome, a rare genetic disorder characterized by premature closure of coronal sutures, results in skull and facial deformities along with abnormal brain and ocular development. CASE PRESENTATION: Here, we report a case of a 27-year-old ethnic han male patient who presented with complex binocular strabismus secondary to Crouzon syndrome. At the time of surgery, extraocular muscles were found to be fibrotic and results of the pathological examination revealed degeneration of muscle fibers, which were replaced by adipose tissue. The entire exome sequencing DNA testing indicated that the patient and his father possessed the fibroblast growth factor receptor 2 (FGFR2) gene c.G812T:p.G271V heterozygous mutation. Binocular strabismus corrective surgery was performed in this patient with a satisfactory outcome. CONCLUSIONS: This case demonstrates that Crouzon syndrome patients can show an FGFR2 gene c.G812T:p.G271V mutation and display clinical symptoms such as extraocular muscle fibrosis, exotropia, exophthalmos, and a pointed head deformity.

Two siblings with GAPO syndrome: Ophthalmic presentation and histopathologic findings.

BACKGROUND: GAPO syndrome (growth retardation, alopecia, pseudoanodontia, optic atrophy) is a rare, autosomal recessive connective tissue disorder with only 60 reported cases. Ophthalmic manifestations vary and include hypertelorism, optic atrophy, and glaucoma. There have been three reported cases of GAPO syndrome with craniosynostosis. MATERIALS/METHODS: We describe two new siblings with GAPO syndrome and craniosynostosis and the first histopathologic analysis of Tenon's capsule and extraocular muscle in this syndrome. RESULTS: Both siblings presented with papilledema and V-pattern strabismus in addition to the alopecia, brittle eyelashes, growth retardation, and pseudoanodontia that characterize GAPO syndrome. Cranial vault expansion, though successful, was complicated by lack of distinct periosteal layers, thin dural adherence to bone, and extensive venous bleeding. Tenons encountered during strabismus surgery was inelastic and highly vascular. Histopathological analysis revealed hyalinization of Tenon's and a thickened, homogenized, amorphous appearance, similar to the extracellular matrix abnormalities described in skin and other organs Histopathological analysis of extraocular muscle was, in contrast, unremarkable. CONCLUSIONS: GAPO impacts the extracellular matrix of Tenon's resulting in inelasticity and hypervascularity. Ophthalmologists should be mindful of these aberrant characteristics when planning surgery in this population.

Ophthalmic manifestations of Lamb-Shaffer syndrome: a case presentation and literature review.

Lamb-Shaffer syndrome, caused by haploinsufficiency of SOX5, leads to a unique constellation of dysmorphic features and intellectual delay. The SOX5 family of proteins plays an integral role in neuronal development. We present the clinical traits of an 11-year-old boy with Lamb-Shaffer syndrome and highlight the ocular findings of the syndrome reported thus far in the literature. Approximately 55% of all patients reviewed had some form of ocular abnormality associated with Lamb-Shaffer syndrome, including, predominantly, strabismus as well as optic nerve abnormalities, epicanthal folds, and refractive errors, highlighting the potential significance of SOX5 on neurologic development.

Complex Autism Spectrum Disorder with Epilepsy, Strabismus and Self-Injurious Behaviors in a Patient with a De Novo Heterozygous POLR2A Variant.

Autism spectrum disorder (ASD) describes a complex and heterogenous group of neurodevelopmental disorders. Whole genome sequencing continues to shed light on the multifactorial etiology of ASD. Dysregulated transcriptional pathways have been implicated in neurodevelopmental disorders. Emerging evidence suggests that de novo POLR2A variants cause a newly described phenotype called 'Neurodevelopmental Disorder with Hypotonia and Variable Intellectual and Behavioral Abnormalities' (NEDHIB). The variable phenotype manifests with a spectrum of features; primarily early onset hypotonia and delay in developmental milestones. In this study, we investigate a patient with complex ASD involving epilepsy and strabismus. Whole genome sequencing of the proband−parent trio uncovered a novel de novo POLR2A variant (c.1367T>C, p. Val456Ala) in the proband. The variant appears deleterious according to in silico tools. We describe the phenotype in our patient, who is now 31 years old, draw connections between the previously reported phenotypes and further delineate this emerging neurodevelopmental phenotype. This study sheds new insights into this neurodevelopmental disorder, and more broadly, the genetic etiology of ASD.

Missense mutation in the PAX6 gene can cause a complex mild variable phenotype predominated by concomitant strabismus.

PURPOSE: We aimed to reveal the underlying genetic defect in a multigenerational Chinese family with autosomal dominant concomitant strabismus complicated by multiple ocular developmental abnormalities. METHODS: Comprehensive ophthalmic examinations were performed in 14 patients and 24 healthy family members. Whole exome sequencing was performed, and Sanger sequencing was used to confirm the probable mutation in all the family members. RESULTS: Concomitant strabismus was the predominant phenotype in the affected family members, although the patients also exhibited variable phenotypes, including nystagmus, mild iris abnormalities, myopia, cataract, and coloboma. An R208W mutation in PAX6 was identified as the pathogenic mutation in the affected family members. CONCLUSIONS: We recommend considering PAX6 as a candidate gene in the diagnostic screen for familial concomitant strabismus in order to avoid missed diagnosis of the mild ocular abnormalities. Careful examinations of mild ocular phenotypes are necessary for an accurate diagnosis of varied ocular abnormalities in the families with the PAX6 mutation, and proper diagnosis can facilitate genetic and clinical counseling for affected patients.

Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant.

Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wide variant calling approach, despite being located in protein coding sequence. More detailed analysis revealed that the position of the variant within exon 5 of TUBB3 was not targeted by the enrichment kit, although consistent high-quality coverage was obtained at this position, resulting from nearby targets that provide off-target coverage. In the initial analysis, variant calling was restricted to the exon targets ± 200 bases, allowing the variant to escape detection by the variant calling algorithm. This phenomenon may potentially occur more often, as we determined that 36 established ID genes have robust off-target coverage in coding sequence. Moreover, within these regions, for 17 genes (likely) pathogenic variants have been identified before. Therefore, this clinical report highlights that, although compute-intensive, performing genome-wide variant calling instead of target-based calling may lead to the detection of diagnostically relevant variants that would otherwise remain unnoticed.

Commonly occurring genetic polymorphisms with a major impact on the risk of nonsyndromic strabismus: replication in a sample from Finland.

PURPOSE: To replicate associations between polymorphisms in the WRB and TSPAN10 genes and strabismus in an independent Finnish cohort and to calculate their population attributable risk. METHODS: Polymorphisms in the WRB (rs2244352) and TSPAN10 (rs6420484) genes were investigated in individuals from the FinnGen study group who had one of three categories of strabismus, with clinical diagnoses of (1) "strabismus-all subtypes" (3,515 cases and 173,384 controls), (2) "convergent concomitant strabismus" (ICD-10 code H50.0; 737 cases and 170,976 controls), and (3) "divergent concomitant strabismus" (ICD-10 code H50.1; 1,059 cases and 170,976 controls). RESULTS: The WRB polymorphism was associated with "all subtypes" of strabismus (OR = 1.08; P = 0.008) and divergent strabismus (OR = 1.11; P = 0.046) but not with convergent strabismus (P = 0.41). The WRB polymorphism had a population attributable risk of 3.4% for all strabismus subtypes and 4.7% for divergent strabismus. The TSPAN10 polymorphism was associated with all three strabismus phenotypes: "all subtypes" (OR = 1.08; P = 0.002), convergent strabismus (OR = 1.19; P = 0.001) and divergent strabismus (OR = 1.20; P =7.21E-05). The population attributable risk for the TSPAN10 polymorphism was 6.0% for any strabismus, 13.3% for convergent strabismus, and 13.9% for divergent strabismus. CONCLUSIONS: Genetic association with strabismus was replicated in a Finnish cohort for two common polymorphisms. Under the assumption that these polymorphisms are independent of other risk factors, they are responsible for up to 20% of isolated cases of strabismus in Finland, similar to estimates in other European populations.

Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region.

Strabismus is a common condition, affecting 1%-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis. Among these, nine are affected and four are unaffected. A single linkage signal has been identified at an 8.5 Mb region of chromosome 14q12 with a multipoint LOD (logarithm of the odds) score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next-generation sequencing and in-depth bioinformatic analyses, a 4 bp non-coding deletion was prioritised as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of FOXG1, which encodes a transcription factor of the Forkhead family. Suggestive of an autoregulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. Future study of this specific deletion may shed light on the regulation of FOXG1 expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.

Genotype-phenotype correlations in ocular manifestations of Marinesco-Sjögren syndrome: Case report and literature review.

PURPOSE: This study aims to present a family with two children with MSS who presented with different ophthalmic features. We also aim to review MSS patients' ocular manifestations to provide a basis for future clinical trials and improve MSS patients' ophthalmologic care. CASE DESCRIPTION: Both patients presented with global developmental delay, microcephaly, cerebellar ataxia, and myopathy. The older sibling had developed bilateral cataracts at the age of six. Her 2 years younger sister interestingly showed bilateral hyperopic refractive error without cataracts yet. Mendeliome sequencing unraveled a novel homozygous frameshift mutation in the SIL1 gene (SIL1, NM_022464.5, c.1042dupG, p.E348Gfs*4), causing MSS. A systematic literature review revealed that cataracts appear in 96% of MSS cases with a mean onset at 3.2 years. Additional frequent ocular features were strabismus (51.6%) and nystagmus (45.2%). CONCLUSION: SIL1-related MSS is associated with marked clinical variability. Cataracts can develop later than neuromuscular features and cognitive signs. Since cataract is a relatively late finding, patients may refer to ophthalmologists for other reasons such as refractive errors, strabismus, or nystagmus. Molecular genetic testing for SIL1 is essential to facilitate early diagnosis in patients with suspected MSS.

Expanding the phenotypic spectrum of mutations in LRP2: a novel candidate gene of non-syndromic familial comitant strabismus.

BACKGROUND: Comitant strabismus (CS) is a heterogeneous disorder that is a major contributing factor to unilateral childhood-onset visual impairment. Studies have confirmed that genetic factors play an important role in the development of CS. The aim of this study was to identify the genetic cause of non-syndromic familial CS. METHODS: Fourteen unrelated CS families were recruited for the study. Twelve affected and 2 unaffected individuals from a large four-generation family (CS08) were selected to perform whole genome-wide linkage analysis. Parallel whole-exome sequencing (WES) was conducted in the same family (9 patients and 1 unaffected member) and 31 additional CS cases from 13 other unrelated families. Sanger sequencing was used to determine whether any of the remaining variants co-segregated with the disease phenotype in the corresponding family. RESULTS: Based on linkage analysis, CS in family CS08 mapped to a novel region of 34.17 centimorgan (cM) on chromosome 2q22.3-2q32.1 between markers D2S151 and D2S364, with a maximum log odds (LOD) score of 3.54 (theta = 0) at D2S142. Parallel WES identified a heterozygous variant, LRP2 c.335 A > G (p.Q112R), located in such a linkage interval that completely co-segregated with the disease in the family. Furthermore, another novel heterozygous variant (c.7274A > G, p.D2425G) in LRP2 that co-segregated was detected in 2 additional affected individuals from another unrelated family by WES. Both variants are predicted to be damaging by PolyPhen-2, SIFT and MutationTaster, and were absent in 100 ethnically matched normal controls. CONCLUSION: LRP2 is a novel candidate genetic cause of non-syndromic familial CS.

CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental delay, strabismus, behavioural problems and skeletal anomalies.

In a consanguineous Pakistani kinship afflicted with mild to moderate intellectual disability (ID), mild lissencephaly, brain atrophy and skeletal anomalies, we detected homozygous CRADD c.2T > G (p.Met1?) and USP44 c.873_886delinsT (p.Leu291Phefs*8), two good candidates 1.85-Mb apart that segregated with the disorder. Biallelic damaging variants in CRADD cause recessive mental retardation-34 (MRT34; MIM 614499) with mild to moderate ID, "thin" lissencephaly, and variable megalencephaly and seizures. For USP44, only a single ID family has been reported with a homozygous deleterious variant, which is the same as the variant we detected. In affected individuals we present, at ages 29-32 years, clinical findings are similar yet not fully concordant with phenotypes for either gene considering the skeletal findings, and ID is not as severe as would be expected for defects in two genes with additive effect. Some variable CRADD-related features such as language impairment and seizures are not observed in the presented family. The presence of the two variants in the family is a very rare example of familial linked homozygous variants, and whether the damaging USP44 variant contributed to the disease in the family we present is not clear. As for the skeletal findings, facial dysmorphism and digestive problems, we did not find a candidate variant. This study is an example of both clinical variation and difficulty in variant detection and evaluation. Our findings highlight that even an extensive exome sequence analysis can fail to fully uncover the complex molecular basis of a syndrome even if potentially causative variants are identified.

Ocular Phenotype Associated with DYRK1A Variants.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A or DYRK1A, contributes to central nervous system development in a dose-sensitive manner. Triallelic DYRK1A is implicated in the neuropathology of Down syndrome, whereas haploinsufficiency causes the rare DYRK1A-related intellectual disability syndrome (also known as mental retardation 7). It is characterised by intellectual disability, autism spectrum disorder and microcephaly with a typical facial gestalt. Preclinical studies elucidate a role for DYRK1A in eye development and case studies have reported associated ocular pathology. In this study families of the DYRK1A Syndrome International Association were asked to self-report any co-existing ocular abnormalities. Twenty-six patients responded but only 14 had molecular confirmation of a DYRK1A pathogenic variant. A further nineteen patients from the UK Genomics England 100,000 Genomes Project were identified and combined with 112 patients reported in the literature for further analysis. Ninety out of 145 patients (62.1%) with heterozygous DYRK1A variants revealed ocular features, these ranged from optic nerve hypoplasia (13%, 12/90), refractive error (35.6%, 32/90) and strabismus (21.1%, 19/90). Patients with DYRK1A variants should be referred to ophthalmology as part of their management care pathway to prevent amblyopia in children and reduce visual comorbidity, which may further impact on learning, behaviour, and quality of life.

Molecular Pathways within Autism Spectrum Disorder Endophenotypes.

Autism spectrum disorder (ASD) is a condition that includes a number of neurodevelopmental mental disorders. Recent genetic/genomic investigations have reported an increased prevalence of copy number variations (CNVs) in individuals with autism. Despite the extensive evidence of a genetic component, the genes involved are not known and the background is heterogeneous among subjects. As such, it is highly likely that multiple events (molecular cascades) are implicated in the development of autism. The aim of this work was to shed some light on the biological background behind this condition. We hypothesized that the heterogeneous alterations found within different individuals may converge into one or more specific biological functions (pathways) linked to the heterogeneous phenotypes commonly observed in subjects with ASD. We analyzed a sample of 107 individuals for CNV alterations and checked the genes located within the altered loci (1366). Then, we characterized the subjects for distinct phenotypes. After creating subsamples based on symptoms, the CNVs related to each specific symptom were used to create distinct networks associated with each phenotype (18 in total in the sample under analysis). These networks were independently clustered and enriched to identify potential common pathways involved in autism and variably combined with the clinical phenotype. The first 10 pathways of the analysis are discussed.

Identification of Possible Risk Variants of Familial Strabismus Using Exome Sequencing Analysis.

PURPOSE: To investigate candidate genes associated with familial strabismus and propose a theory of their interaction in familial strabismus associated with early neurodevelopment. METHODS: Eighteen families, including 53 patients diagnosed with strabismus and 34 unaffected family members, were analyzed. All patients with strabismus and available unaffected family members were evaluated using whole exome sequencing. The primary outcome was to identify rare occurring variants among affected individuals and investigate the evidence of their genetic heterogeneity. These results were compared with exome sequencing analysis to build a comprehensive genetic profile of the study families. RESULTS: We observed 60 variants from 58 genes in 53 patients diagnosed with strabismus. We prioritized the most credible risk variants, which showed clear segregation in family members affected by strabismus. As a result, we found risk variants in four genes (FAT3, KCNH2, CELSR1, and TTYH1) in five families, suggesting their role in development of familial strabismus. In other families, there were several rare genetic variants in affected cases, but we did not find clear segregation pattern across family members. CONCLUSION: Genomic sequencing holds great promise in elucidating the genetic causes of strabismus; further research with larger cohorts or other related approaches are warranted.

Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization.

Neuroligin 4 X-linked (NLGN4X) is an X-linked postsynaptic scaffolding protein, with functional role in excitatory synapsis development and maintenance, that has been associated with neuropsychiatric disorders such as intellectual disability, autism spectrum disorders (ASD), anxiety, attention deficit hyperactivity disorder (ADHD), and Tourette's syndrome. Chromosomal microarray analysis identified a paternally inherited, 445 Kb deletion on Xp22.3 that includes the entire NLGN4X in a 2.5 year old female (46,XX) with congenital hypotonia, strabismus, ASD, and increased aggressive behavioral issues. Her family history is significant for a mother with learning disabilities, a father with anxiety, major depressive disorder, and substance abuse, as well as two maternal half-brothers with developmental delays. X-inactivation studies in the proband's blood showed random X-inactivation despite the presence of an abnormal X chromosome. Furthermore, trio exome sequencing did not reveal any other deleterious variant that could explain her phenotype. Our report describes the first example of a paternally inherited NLGN4X microdeletion as the genetic etiology of ASD in a female proband, and the psychiatric phenotypes in the father. It also provides further evidence that NLGN4X is sensitive to dosage changes in females, and can contribute to a variety of psychiatric features within the same family.

High Myopia and Strabismus Induced by a Deep Intronic Mutation in COL2A1.

Purpose: To characterize a genetic mutation causing Stickler syndrome in a previously undiagnosed family.Methods: Five generations of a single family suspected of having Stickler syndrome were evaluated clinically and genetically.Results: The demographic and clinical data yielded specific clinical phenotypes of Stickler syndrome in 13 family members; 7 had more than one clinical feature. Four family members underwent genetic analysis: the proband (index patient) and his mother, maternal grandfather, and healthy father. No relevant mutation was detected in the proband on whole exome analysis, but subsequent extension of the analysis to intronic areas yielded a deep intronic mutation, NM_001844.5:c.1527 + 135 G > A. Sanger sequencing was used to validate the results in the family members.Conclusions: Stickler syndrome has several subtypes with variable clinical features. Therefore, predicting the genetic locus of the disease based on clinical characteristics is challenging. We present a rarely described intronic mutation in COL2A1. Genetic testing may aid in the early diagnosis of Stickler syndrome, which is important for genetic counselling, proper clinical management, and improved prognosis.

Adrenoleukodystrophy siblings with a novel ABCD1 missense variant presenting with phenotypic differences: a case report and literature review.

Adrenoleukodystrophy (ALD) is an X-linked disease that affects primarily the white matter of the central nervous system and adrenal cortex. A correlation between genotypes and phenotypes has not been observed. Here, we present two Japanese siblings with a novel missense variant (c.1887T > G) in the ABCD1 gene who presented with different clinical phenotypes, i.e., adolescent cerebral and cerebello-brainstem types. We also review the literature focusing on the variation in the clinical phenotypes within ALD families. In our review, 61.9% of sibling pairs presented with the same clinical type of ALD and 59.1% of sibling pairs presented with a similar age of onset. Conversely, 15.4% of sibling pairs had a similar age of onset, but different clinical types of ALD. To observe the correlation between genotypes and phenotypes, it is important to diagnose early and to accumulate reports describing age of onset, first onset symptom, and progression of the symptom.

The Role of Heredity and the Prevalence of Strabismus in Families with Accommodative, Partial Accommodative, and Infantile Esotropia

Objectives: To investigate the prevalence of strabismus in families of a proband with accommodative, partial accommodative, or infantile esotropia, and to evaluate the mode of inheritance and the role of consanguineous marriages in this prevalence. Materials and Methods: Families of probands with comitant strabismus were invited to participate in the study. The family members of 139 subjects with accommodative, 55 with partial accommodative, and 21 with infantile esotropia agreed to participate. Detailed family trees were constructed. The first- and second-degree relatives were invited for a complete ophthalmological examination, and 518 individuals from 168 families were evaluated. The role of consanguinity, the presence of tropia, phoria (≥8 PD), microtropia, and hypermetropia (≥3.00 D) among first- and second-degree relatives were analyzed. Results: A non-Mendelian pattern was found in 49 families (23%), an autosomal dominant pattern in 39 families (18%), and an autosomal recessive pattern in 6 families (3%). The prevalence of consanguineous marriages among parents of probands was 18.1%, 22.6%, and 14.3% in the accommodative, partial accommodative, and infantile esotropia groups, respectively (p=0.652). The prevalence of strabismus in first-degree relatives was 58.9%, 45.5%, and 38.1%, respectively (p=0.07). The prevalence of microtropia in probands' siblings was significantly higher in the accommodative esotropia group (p=0.034). Conclusion: Sporadic cases and non-Mendelian inheritance were more frequent than autosomal recessive inheritance. Autosomal recessive inheritance was found not to be frequent in consanguineous marriages. The prevalence of strabismus and microtropia was significantly higher in families of esotropia cases than in the general population.