Adapting international clinical practice guidelines for rehabilitation management of acute spinal cord injury in Iran.

Infantile nystagmus (IN, also known as congenital nystagmus) is a broad clinical term referring to disorders characterised by involuntary, rhythmic oscillations of the eyes that typically present within the first six months of life. It has an estimated prevalence of approximately 6.1 per 10,000 live births, depending on the population studied. IN is a genetically and phenotypically heterogeneous condition, often associated with developmental abnormalities of the retina, optic nerve, or brain. While most cases are due to genetic causes - including albinism, inherited retinal disorders, or idiopathic IN - non-genetic aetiologies must be carefully excluded. These include acquired structural brain lesions, such as space-occupying tumours or intracranial malformations, particularly in cases with late-onset or asymmetric findings. Early and accurate classification of IN is therefore crucial, not only to guide appropriate investigations and genetic testing, but also to identify syndromic associations that may have broader clinical implications. IN frequently co-occurs with conditions affecting the fovea or optic pathway, most notably albinism. Albinism refers to a group of genetic disorders of melanin biosynthesis characterised by hypopigmentation of the eyes, and often the skin and hair. In albinism, absent or reduced pigmentation leads to structural eye abnormalities such as foveal hypoplasia and optic nerve misrouting. The genetic architecture of albinism is also highly heterogeneous. There are multiple oculocutaneous albinism (OCA) subtypes, primarily caused by autosomal recessive variants in genes such as (OCA1), (OCA2), and others. In European populations, and together account for roughly 70% of OCA cases . X-linked ocular albinism (OA1) is caused by variants and constitutes around 7% of albinism cases. The remaining cases are explained by less common genes including those associated with Hermansky–Pudlak syndrome and other rare forms. Because infantile nystagmus can be a unifying presentation, patients are often initially labelled under broad terms (e.g., “nystagmus” or “albinism”) even though the underlying genotypes span dozens of genes. Traditional diagnostic approaches, such as targeted gene panels, may focus on the most common genes for a presumed diagnosis (for example, an “albinism” gene panel) and could miss atypical or syndromic causes. Advances in genomic medicine, particularly a disease-agnostic analysis of whole-genome sequencing (WGS) data, enables a more comprehensive investigation of patients with genetically heterogeneous conditions. WGS captures sequence information across the entire genome, including coding regions, splice sites, and non-coding regulatory elements. In clinical practice, in silico targeted panel analysis of WGS data has proven both sensitive and time-efficient, enabling phenotype-driven variant identification while maintaining the flexibility to investigate off-panel genes when initial analysis is non-diagnostic. Furthermore, large initiatives like the UK’s 100,000 Genomes Project (100KGP) provide an opportunity to study genotype–phenotype relationships at scale. Early studies from the 100KGP and other WGS cohorts have reported diagnostic yields around 25–40% across diverse rare diseases, but certain ophthalmic conditions may achieve higher yields with careful phenotypic selection. A recent review of genetic testing in infantile nystagmus syndrome found molecular diagnosis rates of 35–60% using targeted panels, which rose to ~80% when testing was guided by specific clinical findings (and up to 88% with a positive family history) . Moreover, genetic results can refine the clinical diagnosis in up to 30% of patients, highlighting the importance of genomic analysis for appropriate patient classification. In this study, we utilised the nationwide 100KGP dataset to investigate infants and children with nystagmus and albinism phenotypes. Our aims were to (1) determine the diagnostic yield of in silico panel analysis of WGS data in this cohort, (2) characterize the spectrum of genetic variants, including novel and recurrent mutations, and (3) explore genotype–phenotype correlations by integrating detailed clinical data (Human Phenotype Ontology terms, ICD-10 codes, and rare disease categories). We hypothesized that a combined analysis of genomic and phenotypic data would not only improve diagnostic discovery but also reveal patterns (e.g., specific co-occurring features) that could help clinicians distinguish among genetic causes of infantile nystagmus and albinism.