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ABSTRACT SUMOylation involves covalent attachment of small ubiquitin‐like modifier (SUMO) proteins to specific lysine residues on target proteins and regulates various aspects of their function. Sentrin‐specific proteases (SENPs) are key players in both the conjugation reaction of SUMO proteins to their targets and the subsequent deconjugation of SUMO‐conjugated substrates. Here, we provide the first comprehensive prenatal description of a lethal syndrome linked to a novel homozygous stop‐gain variant in SENP7 c.745C>T; p.(Arg249*) in a consanguineous Egyptian family with a history of three fetal deaths, all presenting with multiple congenital anomalies. Similar anomalies were observed through ultrasound assessment of the current fetus, including arthrogryposis multiplex congenita, CNS malformations, congenital heart disease, and renal anomalies. Singleton exome sequencing (ES) of fetal DNA revealed a SENP7 variant allele, which results in a premature termination codon, and the mutant mRNA is predicted to be degraded by nonsense‐mediated decay (NMD). This leads to impaired gene function, particularly disrupting SENP7's isopeptidase activity in deconjugating polySUMO chains. Our findings broaden the molecular spectrum of SENP7 variants and emphasize their essential role in the development of the nervous, musculoskeletal, cardiovascular, and renal systems. This study offers new insights into the genotype–phenotype correlations observed in lethal congenital contracture syndromes and severe embryological abnormalities. [ABSTRACT FROM AUTHOR]

Optic nerve coloboma combined with renal disease, also called renal-coloboma syndrome (#120330 in McKusick's Mendelian Inheritance in Man Online, OMIM), a relatively recently characterized syndrome, results from autosomal dominant mutations in the PAX2 gene. Although renal-coloboma syndrome involves both ocular and renal anomalies, some patients are affected with vesico-ureteral reflux (VUR), high frequency hearing loss, central nervous system (CNS) anomalies, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development. We review here the clinical features of patients with renal-coloboma syndrome and PAX2 mutation. We also review the PAX2 mutations that have been reported to date, and discuss the possible effect of PAX2 mutations on normal development. [ABSTRACT FROM AUTHOR]