ClinVar Genomic variation as it relates to human health

This CNV is a 8.2 Mb duplication of Xq22.3q23 on chromosome X, (seq[GRCh37]dup(X)(q22.3q23); chrX:g.104782507_112949573dup) that was inherited from an unaffected parent but also identified in additional affected family members. The CNV constitutes a gain encompassing 54 genes, of which 45 are protein-coding. One breakpoint resides in an intergenic region, while the other affects the IL1RAPL2 gene, which currently has no established gene-disease relationship. Patients with similar gains in this region have not been reported in the peer-reviewed literature. This CNV is also absent from the Genome Aggregation Database and from control populations in a developmental delay study (Coe et al. 2014). There are several individuals described in the literature with duplications in this region that partially overlap with this CNV. Jehee et al. (2005) report on a 4-year-old boy with FG syndrome and a maternally inherited 4 Mb gain at Xq22.3. His features included prematurity, hypotonia, intellectual disability, developmental delay, epicanthic folds, up-slanted palpebral fissures, short nose with depressed bridge and upturned nares, long philtrum, diastema of upper central incisors, strabismus, hypospadias, constipation, and habitually elevated body temperature. Another report describes a hemizygous 6.7 Mb duplication of Xq22.2q22.3 in a male infant with IUGR, nystagmus, titubation, and spasticity, who later was noted to have growth deficiency, gastrointestinal issues, and developmental delay among other features (Chanchani et al. 2019). Authors note that PLP1 and MID2 are likely contributors to the individual's main features. Of note, PLP1 is not affected by this CNV. A complex rearrangement with a larger ~11 Mb CNV gain including the PLP1 gene and a smaller ~56 kb duplication separated by 160 kb non-duplicated, or normal copy number, genomic interval, is reported in a male child with Pelizaeus-Merzbacher disease, and three females from the family noted to be manifesting carriers (Carvalho et al. 2012). X-inactivation studies showed skewed inactivation pattern in buccal cells. Phenotypes reported in this family include global developmental delay, failure to thrive, nystagmus, hypotonia, hyperreflexia, white matter abnormalities on brain MRI, and facial dysmorphism. Additionally, several copy-number gains with limited overlap in genomic content are found in DECIPHER database in individuals noted to display some overlapping phenotypic features, including intellectual disability, delayed speech and language development, abnormal facial features, and abnormal behavior (Firth et al. 2009). Based on the available evidence, this CNV is classified as likely pathogenic.