الفهرس 
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Abstract
Several developmental and regulatory genes are known to contribute to eye formation during embryogenesis. Disruption of any of these genes during the early stages of eye development can result in either an absent eye (anophthalmia) or a small underdeveloped eye (microphthalmia).
Anophthalmia and microphthalmia (A/M) constitutes a spectrum of developmental ocular disorders that can be caused by chromosomal aberrations, copy number variations and single gene mutations, besides environmental factors. Wide genetic heterogeneity, which is still expanding with molecular testing advances, together with variation in expression, incomplete penetrance and overlapping phenotypes, make diagnosis and genetic counseling very challenging.
A/M may present as an isolated anomaly (non-syndromic) or associated with other extraocular anomalies (syndromic). Syndromic A/M represents the greater proportion of cases and is also known to have higher identifiable genetic causes and higher diagnostic rates.
Aiming to gain insight into genetic etiologies and to study the clinical characteristics of A/M in the Egyptian population, we recruited 45 patients with A/M from 39 unrelated Egyptian families from the Genetic Clinic of Human Genetics Department, Medical Research Institute, and Pediatric Ophthalmology Outpatient Clinic of Alexandria University Hospital of Faculty of Medicine, Alexandria University. All the patients were subjected to detailed genetic history taking, pregnancy and delivery history, full ophthalmological assessment, complete clinical genetic examination, pedigree analysis, clinical photography, chromosomal analysis and molecular analysis according to individual cases.
Environmental factors were identified in 3 patients who were thus, excluded from further genetic testing. The remaining 42 patients were divided into two groups based on their clinical assessment: isolated A/M (20 cases) and syndromic A/M (22 cases).
The group of isolated A/M included 20 cases (from 14 families) who presented with isolated AM without other systemic involvement. This group was further subcategorized into:
- Complex isolated A/M: 16/20 (80%) were classified as complex cases due to their association with other ocular abnormalities within the affected or the contralateral eye.
- Simple isolated A/M: 4/20 (20%) presented with A/M with no other ocular anomalies.
Among this group, five of the 12 families who underwent molecular testing (41.6%) had an identifiable genetic cause, whereas in the remaining cases, no genetic etiology could be determined. Among the solved cases, pathogenic and likely-pathogenic variants in the ATOH7, GJA8 and PRR12 genes have been identified, each in a single family. On the other hand, two variants of uncertain significance (in OTX2 and GCNT2 gene), with strong evidence supporting their pathogenicity, were found in another two families.
On the other hand, the syndromic A/M group consisted of 22 A/M cases presenting with extra ocular and systemic manifestations. Cases among this group were subclassified into:
I. Syndromic A/M with chromosomal anomalies: Four cases with clinical features suggestive of Trisomy 13, which was confirmed by karyotyping.
II. Molecularly diagnosed A/M syndromes: Molecular analysis of eight patients revealed underlying disease-causing mutations that confirmed the provisional clinical diagnosis. This group comprised 2 cases of PDAC / MATTHEW-WOOD Syndrome and a single case of each of the following: SOX2 Disorders (Anophthalmia-Esophageal -Genital syndrome), charGE syndrome, oculo-auricular syndrome, developmental delay with short stature, dysmorphic facial features, and sparse hair, intellectual developmental disorder, autosomal recessive 69; Mrt69 and congenital muscular dystrophy with brain and eye anomalies, type A, 11.
III. Clinically diagnosed A/M syndromes: The group included five patients with a provisional clinical diagnosis of charGE syndrome, oculodentodigital syndrome, OAVS (2 cases) and Warburg Micro Syndrome.
IV. Unrecognizable syndromes: A group of 5 patients who lacked the clinical characteristics of a certain genetic syndrome remained unsolved even after conducting cytogenetic and molecular studies.
Collectively, a higher diagnostic yield was obtained in the group of patients with syndromic A/M compared to those presenting with isolated A/M since 77.2% of the syndromic cohort had a definite diagnosis, compared to 41.6% of the isolated cohort.