OFD1 – Simpson-Golabi-Behmel syndrome type 2

X-linked recessive inheritance of loss-of-function variants in OFD1 causes Simpson-Golabi-Behmel syndrome type 2 (Simpson-Golabi-Behmel syndrome type 2). Two unrelated male probands with hemizygous OFD1 disruption have been described: one with a whole-gene deletion detected by array CGH in a male fetus presenting with left-sided congenital diaphragmatic hernia and overgrowth (PMID:27589329); and one male carrying a heterozygous nonsense variant p.Gln892Ter who exhibited SGBS2-like features (PMID:39766900).

Mechanistically, OFD1 haploinsufficiency perturbs primary cilia function, consistent with overlapping features of other OFD1-related ciliopathies. No dedicated functional assays for SGBS2 have been reported; however, studies of OFD1 splice and truncating mutations demonstrate reduced expression and ciliary defects in patient cells, supporting a loss-of-function mechanism.

ClinGen classification: Limited genetic evidence (2 probands, no segregation) and limited experimental data. Key take-home: OFD1 should be included in diagnostic testing for male fetuses with prenatal overgrowth and diaphragmatic hernia.

References

• Prenatal diagnosis • 2016 • Whole exome sequencing and array-based molecular karyotyping as aids to prenatal diagnosis in fetuses with suspected Simpson-Golabi-Behmel syndrome. PMID:27589329
• Genes • 2024 • Expanding the Genotypic and Phenotypic Spectrum of OFD1-Related Conditions: Three More Cases. PMID:39766900

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