Xq26.2 Contiguous Gene Deletion Involving FRMD7 and IGSF1: Highly Penetrant Infantile Nystagmus with Variable Endocrine Involvement

Abstract

Background/Objectives: Contiguous Xq26.2 deletions involving FRMD7 and IGSF1 are rare and incompletely characterized. FRMD7 loss causes X-linked idiopathic infantile nystagmus (IIN), whereas IGSF1 loss causes central hypothyroidism and other pituitary-related abnormalities. We aimed to define the clinical and molecular spectrum of an Xq26.2 contiguous gene deletion in a large Bedouin kindred with infantile nystagmus. Methods: We clinically evaluated ten family members (3 males and 7 females); genomic analyses included chromosomal microarrays, whole-exome and whole-genome sequencing, breakpoint PCR, and Sanger sequencing. Results: We identified a novel 1.44-Mb Xq26.1-q26.2 deletion, NC_000023.11:g.130756102_132199443del (GRCh38), encompassing complete loss of FRMD7, IGSF1, ARHGAP36, OR13H1, and STK26 and partial deletion of the 5′ end of ENOX2. The deletion was molecularly confirmed in six family members. The kindred exhibited a broad phenotypic spectrum, from an asymptomatic confirmed female carrier to isolated nystagmus and combined ocular–endocrine manifestations. Nystagmus was highly penetrant, whereas endocrine abnormalities were less frequent and variable. Hypoprolactinemia occurred in one confirmed female carrier, and a confirmed hemizygous boy had low-normal free T4 without overt central hypothyroidism. The only relative with overt central hypothyroidism was not genotyped; therefore, co-segregation could not be established. Conclusions: These findings further delineate the clinical spectrum of Xq26.2 deletions, highlight marked intrafamilial variability, and support structural variant analysis in unexplained IIN and/or endocrine abnormalities. Longitudinal endocrine assessment of individuals with Xq26.2 deletions and at-risk relatives in affected families may enable early detection and treatment of hypothyroidism.