Clinical spectrum of male patients with OFD1 mutations

Abstract

Oral-facial-digital syndrome type 1 (OFD1) is a ciliopathy characterized by oral, facial, and digital malformations that are often accompanied by polycystic lesion of the kidney and central nervous involvement. OFD1 shows an X-linked recessive inheritance caused by mutation in the OFD1 gene (Xp22.2). The disease is generally considered embryonic lethal for hemizygous males. However, males with OFD1 mutations were recently reported. Here, we report four additional Japanese male patients with OFD1 variants and describe the variable clinical manifestation and disease severity among the four patients. Patient 1 with pathogenic indels including a 19-bp deletion and 4-bp insertion (c.2600-18_2600delinsACCT) had end-stage renal disease (ESRD) with bilateral cystic kidneys and sensory hearing loss. He showed neither intellectual disability nor facial or digital dysmorphism. Patient 2 with a missense variant in exon 7 (c.539A>T, p.Asp180Val) presented head circumference enlargement, brachydactyly, high-arched palate, micropenis, severe global developmental delay, and ESRD. Patient 3 had a single base substitution at the splice donor site of intron 16 (c.2260+2T>G) causing a 513-bp deletion at the transcript level. The patient had chronic kidney disease and speech delay, but no oral, facial, or digital dysmorphism. 4 His uncle (patient 4) carried the same OFD1 variant and showed ESRD with extra-renal malformations including obesity and micropenis, which was previously diagnosed as Bardet-Biedl syndrome. The OFD1 mutations were not lethal in these four male patients, likely because the three mutations were in-frame or missense. This report provided insights into the onset mechanism and phenotype-genotype association in patients with OFD1 mutations.

Different types of disease‐causing noncoding variants revealed by genomic and gene expression analyses in families with X‐linked intellectual disability

“…This variant caused abnormal splicing, thus introducing a novel exon with a predicted frameshift and reduced OFD1 expression (Webb et al, 2012). The respiratory, retinal, cerebellar, and cognitive features seen in the three affected males in our family fit well with the broader phenotype associated with OFD1 variants in males (Table ) (Sakakibara et al, 2019). This distinctive phenotype and the data from the luciferase assays were critical in confirming that the ARX p.Gly402Arg variant was likely benign.…”

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

“…16 mutations in female NDDs, and (3) feature missense variants with milder allelic impact (e.g. partial LOF) in male NDDs, often maternally inherited (41)(42)(43)(44)(45)(46).…”

Clinical and genetic variability of PAX2-related disorder in the Japanese population

“…Twenty-five probands were analyzed only by direct sequencing, and 432 were analyzed by NGS. We identified the causative genes for CAKUT (such as HNF1B, 14 EYA1, 15 and SALL1), nephronophthisis (such as WDR19 16 and OFD1 17 ), and polycystic kidney disease, in 161 probands. PAX2 pathogenic variants were identified in 38 patients from 30 families (18 familial cases from 10 families and 20 sporadic cases) in 457 probands (6.5%).…”