Usmani-Riazuddin syndrome can have a recognizable phenotype: Report of a novel AP1G1 variant.

Usmani-Riazuddin syndrome (USRISR, MIM# 619548; USRISD, MIM#619467) is a very rare genetic condition. recently associated with deleterious variants in AP1G1 (MIM* 603533). It is characterized by multisystemic involvement including intellectual disability, speech and developmental delay, behavioral anomalies, muscular tone disorders, seizures, limb defects, and unspecified facial gestalt. In this report, we describe this syndrome for the second time, in association to a novel AP1G1 variant identified in a toddler with multisystemic involvement including intellectual disability, speech and developmental delay, behavioral anomalies, arrhythmias, hearing loss, skin changes, and limb defects. Next generation sequencing (NGS) analysis through clinical exome disclosed AP1G1: c.1969C>G (p.Leu657Val), de novo, likely pathogenic variant, according to ACMG classification criteria. Proband's facial features resembled the spectrum of chromatinopathies. Clinical pictures were analyzed and a clinical overlap was supported by DeepGestalt analysis (www.face2gene.com). The system identified 6 chromatin disorders out of 30 possible diagnoses. The remaining 24 included 9 miscellaneous cryptic chromosomal abnormalities (excluded due to normal microarray study). To the best of our knowledge, this is the first description of likely distinctive facial features in a patient with Usmani-Riazuddin syndrome. Further multicentric analyses are needed for a better definition of this aspect.

A patient with mosaic USP9X gene variant.

The finding of USP9X variants in females has been associated with female-restricted X-linked mental retardation (MRXS99F), a rare syndrome featured by developmental delay and distinct congenital anomalies. Here, we report a female fetus with MRXS99F due to a novel frameshift variant, c.6679_6685delAAATTATinsTCCTG (p.Lys2227SerfsTer2) in USP9X, which was present in a mosaic state in the amniocytes and in the peripheral blood after birth (14% and 30%, respectively). The X methylation status analysis displayed a partially skewed X-inactivation with 80% of inactive paternal X. The first signs of the MRXS99F were prenatally detected at 20 weeks, with an enlarged posterior cranial fossa, an upward rotation of the cerebellar vermis and partial corpus callosum agenesis, together with a cardiac septal defect and a single umbilical artery. After birth and during postnatal follow-up the anal anteriorization and the presence of a bilateral membranous choanal atresia were noted, whereas the MRI revealed the hypo/aplasia of the olfactory bulbs, a widening of the subarachnoid spaces and a delay in the myelinisation. During the 18-months follow-up a severe growth and global developmental delay, together with a bilateral moderate deafness with a threshold at 40 dB, dental enamel erosions and an initial scoliosis were observed. We report the prenatal and postnatal features of a classical MRXS99F phenotype and a mosaic USP9X frameshift variant with a partially skewed X inactivation and discuss genotype/phenotype correlations in view of the published studies so far.