Prenatal diagnosis of Norrie disease after whole exome sequencing of an affected proband during an ongoing pregnancy: a case report

Abstract

Background Hereditary ophthalmic pathology is a genetically heterogeneous group of diseases that occur either as an isolated eye disorder or as a symptom of hereditary syndromes (chromosomal or monogenic). Thus, a diagnostic search in some cases of ophthalmic pathology can be time- and cost-consuming. The most challenging situation can arise when prenatal diagnosis is needed during an ongoing pregnancy. Case presentation A family was referred to the Research Centre for Medical Genetics (RCMG) for childbirth risk prognosis at 7–8 week of gestation because a previous child, a six-year-old boy, has congenital aniridia, glaucoma, retinal detachment, severe psychomotor delay, and lack of speech and has had several ophthalmic surgeries. The affected child had been previously tested for PAX6 mutations and 11p13 copy number variations, which revealed no changes. Considering the lack of pathogenic changes and precise diagnosis for the affected boy, NGS sequencing of clinically relevant genes was performed for the ongoing pregnancy; it revealed a novel hemizygous substitution NM_000266.3(NDP):c.385G > T, p.(Glu129*), in the NDP gene, which is associated with Norrie disease (OMIM #310600). Subsequent Sanger validation of the affected boy and his mother confirmed the identified substitution inherited in X-linked recessive mode. Amniotic fluid testing revealed the fetus was hemizygous for the variant and lead to the decision of the family to interrupt the pregnancy. Complications which developed during the termination of pregnancy required hysterectomy due to medical necessity. Conclusions Clinical polymorphism of hereditary ophthalmic pathology can severely complicate establishment of an exact diagnosis and make it time- and cost-consuming. NGS appears to be the method-of-choice in complicated cases, and this could substantially hasten the establishment of a diagnosis and genetic risk estimation.

Hearing Function, Degeneration, and Disease: Spotlight on the Stria Vascularis

“…Norrie disease is often misdiagnosed due to the rarity of the condition and the complexity of symptoms. However, improved genetic testing is facilitating earlier diagnosis (Wu et al, 2017;Marakhonov et al, 2020). Nevertheless, even with an accurate diagnosis, it is not possible to predict when hearing loss may occur for individuals with Norrie disease.…”

Ocular findings and genomics of X-linked recessive disorders: A review

“…Norrie disease (OMIM # 310600) is an X-linked disorder resulting from mutations in the NDP (OMIM # 300658) gene (Xp11.4), leading to blindness in male infants at birth or soon after birth. [ 112 113 114 115 116 117 117 ] NDP comprises of three exons spanning 28 kb and encodes the norrin protein. [ 112 113 114 115 116 117 ] Norrin may play an important role in cell proliferation, adhesion, migration and may participate in Wnt signaling.…”

“…[ 112 113 114 115 116 117 117 ] NDP comprises of three exons spanning 28 kb and encodes the norrin protein. [ 112 113 114 115 116 117 ] Norrin may play an important role in cell proliferation, adhesion, migration and may participate in Wnt signaling. [ 112 113 114 115 116 117 ]…”

“…[ 112 113 114 115 116 117 ] Norrin may play an important role in cell proliferation, adhesion, migration and may participate in Wnt signaling. [ 112 113 114 115 116 117 ]…”

“…Ocular findings include leukocoria, iris atrophy, microphthalmos, synechiae, cataracts and sclerocornea. [ 112 113 114 115 116 117 ] Affected individuals had bilateral retinal folds with retinal detachment and macular traction. [ 115 ] Hemorrhagic necrosis of an undifferentiated glial mass was revealed in histology.…”