Clinical and neurocognitive issues associated with Bosch‐Boonstra‐Schaaf optic atrophy syndrome: A case study

Abstract

Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced nonverbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities. K E Y W O R D S autism, Bosch-Boonstra-Schaaf optic atrophy syndrome, cognitive discrepancy, NR2F1

Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model

“… 27 In the current patient cohort, 22 individuals with pathogenic variants in NR2F1 were investigated, including familial cases. Despite the high prevalence of visual system deficits in previously reported individuals with NR2F1 variants, 9 , 14–18 , 28 there are limited data on the ocular phenotype and the disease mechanisms that contribute to visual loss in affected individuals, since previous reports mainly focussed on the systemic clinical features. 19 , 29 Furthermore, the developmental pattern and timing of NR2F1 expression in different human retinal cell types have not been assessed.…”

NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients

“…This, together with the difficulty of obtaining high‐resolution magnetic resonance imaging (MRI) at young age, has limited the investigation of possible brain malformations, which could correlate with the high frequency of ID (more than 80%) and epileptic seizures (40%) in BBSOAS patients. New reports are constantly expanding the BBSOAS clinical spectrum (Chen et al , ; Martín‐Hernández et al , ; Bojanek et al , ; Park et al , ; Rech et al , ), as more patients are identified and the pathophysiology of different brain regions or different organs starts to be explored.…”

Clinical and genetic charsteristics of the Bosch–Boonstra–Schaaf syndrome due to novel mutations in the <i>NR2F1</i> gene

“…Кроме того, в недавно опубликованной работе E. K. Bojanek и соавт. [10] представлено описание больного мужчины с нонсенс-мутацией с.82С>Т (р.Gln28*) в области N-концевого участка гена NR2F1, клиническая картина которого характеризовалась избирательным нарушением невербальных функций при сохранности речи.…”

“…К настоящему времени описаны 36 мутаций в гене, 24 из которых -однонуклеотидные замены (миссенс / нонсенс-мутации), 11 -делеции различных размеров и 1 -комбинированная хромосомная перестройка с включением локуса гена [1,[4][5][6][7][8]. Обнаружен полиморфизм клинических признаков у больных с различными типами мутаций, нарушающими аминокислотную последовательность отдельных доменов белка, что, по мнению большинства авторов, обусловливает необходимость продолжения исследований, направленных на выявление клинико-генетических корреляций при СББШ [2,9,10]. Результаты таких исследований позволят оптимизировать диагностику заболевания и прогнозировать тяжесть клинических проявлений у больных с различной локализацией и типами мутаций в гене.…”