Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project.

Childhood glaucoma (CG) encompasses a heterogeneous group of genetic eye disorders that is responsible for approximately 5% of childhood blindness worldwide. Understanding the molecular aetiology is key to improving diagnosis, prognosis and unlocking the potential for optimising clinical management. In this study, we investigated 86 CG cases from 78 unrelated families of diverse ethnic backgrounds, recruited into the Genomics England 100,000 Genomes Project (GE100KGP) rare disease cohort, to improve the genetic diagnostic yield. Using the Genomics England/Genomic Medicine Centres (GE/GMC) diagnostic pipeline, 13 unrelated families were solved (13/78, 17%). Further interrogation using an expanded gene panel yielded a molecular diagnosis in 7 more unrelated families (7/78, 9%). This analysis effectively raises the total number of solved CG families in the GE100KGP to 26% (20/78 families). Twenty-five percent (5/20) of the solved families had primary congenital glaucoma (PCG), while 75% (15/20) had secondary CG; 53% of this group had non-acquired ocular anomalies (including iris hypoplasia, megalocornea, ectopia pupillae, retinal dystrophy, and refractive errors) and 47% had non-acquired systemic diseases such as cardiac abnormalities, hearing impairment, and developmental delay. CYP1B1 was the most frequently implicated gene, accounting for 55% (11/20) of the solved families. We identified two novel likely pathogenic variants in the TEK gene, in addition to one novel pathogenic copy number variant (CNV) in FOXC1. Variants that passed undetected in the GE100KGP diagnostic pipeline were likely due to limitations of the tiering process, the use of smaller gene panels during analysis, and the prioritisation of coding SNVs and indels over larger structural variants, CNVs, and non-coding variants.

Identification of a Novel Frameshift Variant in MYF5 Leading to External Ophthalmoplegia with Rib and Vertebral Anomalies.

Myogenic transcription factors with a basic helix-loop-helix (bHLH) such as MYOD, myogenin, MRF4, and MYF5 contribute to muscle differentiation and regulation. The MYF5 gene located on chromosome 12 encodes for myogenic factor 5 (MYF5), which has a role in skeletal and extraocular muscle development and rib formation. Variants in MYF5 were found to cause external ophthalmoplegia with rib and vertebral anomalies (EORVA), a rare recessive condition. To date, three homozygous variants in MYF5 have been reported to cause EORVA in six members of four unrelated families. Here, we present a novel homozygous MYF5 frameshift variant, c.596dupA p. (Asn199Lysfs*49), causing premature protein termination and presenting with external ophthalmoplegia, ptosis, and scoliosis in three siblings from a consanguineous family of Pakistani origin. With four MYF5 variants now discovered, genetic testing and paediatric assessment for extra-ocular features should be considered in all cases of congenital ophthalmoplegia.

Cytomegalovirus Retinitis Screening and Treatment in Human Immunodeficiency Virus Patients in Malawi: A Feasibility Study.

BACKGROUND: Cytomegalovirus retinitis is a treatable cause of blindness in people with human immunodeficiency virus (HIV) typically with CD4 counts <50 cells/mm3. Diagnosis is with indirect fundoscopy, and treatment is with intravitreal ganciclovir injections or systemic therapy. However, diagnosis and treatment are not widely available in Malawi, which has an adult HIV prevalence estimated at 10.6%. This study aimed to establish the prevalence of cytomegalovirus retinitis among people with HIV in Malawi and the feasibility of screening. METHODS: Patients with CD4 counts <200 cells/mm3 were examined from 2 HIV clinics in Lilongwe and the main government hospital. Data were collected on antiretroviral therapy, ocular symptoms, and visual acuity. Fundoscopy was performed to investigate for features of cytomegalovirus retinitis. Retinal photographs were reviewed by an ophthalmologist. Patients diagnosed with cytomegalovirus retinitis were offered weekly ganciclovir injections, because systemic treatment was not available. RESULTS: Five of the 102 people with HIV screened had cytomegalovirus retinitis (4.9%). All affected patients had CD4 counts <50 cells/mm3 (mean, 15 cells/mm3; range, 3-22 cells/mm3). Visual acuity was unhelpful in identifying those with cytomegalovirus retinitis. Symptomatically, only blurred vision was useful. Two patients consented to treatment, 1 of which improved but relapsed after defaulting. CONCLUSIONS: Cytomegalovirus retinitis screening based on CD4 count is essential to early recognition because visual acuity and symptoms are unreliable. Cytomegalovirus retinitis is a significant yet neglected public health issue in Malawi. Oral valganciclovir is essential to reduce blindness and mortality in those diagnosed but is not yet available. Further screening and advocacy are needed.