case_images: PMC11790519_01
case_images: Clinical overview. (A) Family pedigree. (B) Photographs at 16 years (top) and 23 years (bottom). (C) T2-weighted (a, d) and T2-FLAIR (b, c, e) brain-MRI at 6 years (a, e) and 17 years (b-d) in the axial (a-d) or coronal plane (e) showing generalised bilateral white matter abnormalities at supratentorial, right-sided periventricular and subcortical regions and the left-sided frontal area (arrows). Liquor spaces are asymmetrically enlarged without progression. Cerebral CT angiography at 8 years (f), showing bilateral narrowing of the internal carotid arteries, most pronounced on the right and at the T-junction. There is a distinct puff of smoke appearance, with prominent lenticulostriate arteries (arrows).
case_images: CGE-107-341-g001.jpg
case_images: PMC11790519_01_CGE-107-341-g001.jpg
case_images: cge14650-fig-0001
case_images: He was the second child, born to non-consanguineous parents (Figure 1A). At 6 years, examination showed a height of 118 cm (-0.4SD), a weight of 22 kg (+0.4SD) and a head circumference of 54.8 cm (+2SD) as well as dysmorphic features including hypertelorism and bilateral supernumerary nipples (Figure 1B). Furthermore, CTA of the brain showed bilateral stenosis of the internal carotid arteries, interpreted as signs of cerebral vasculitis or moyamoya angiopathy (Figure 1C). Dysmorphic features included hypertelorism, downslanting palpebral fissures, mild proptosis, an elongated face with a prominent chin, small ears, pectus excavatum, bilateral supernumerary nipples, small hands and feet, cubitus valgus and acne-like lesions (Figure 1B).
case_images: RNA-seq identifying a disease-causing Xq28 deletion. (A) Volcano plot showing z-scores at the gene level and log10 (p values) for all assessed genes by RNA-seq in the index. Here, CMC4, MTCP1 and BRCC3 showed the most striking downregulation (z-scores < -10); other genes did not show significant downregulation (z-score < -4), except for ACOT9 (z-score - 8). ACOT9 downregulation is likely caused by a maternally inherited hemizygous frameshift variant. (B) Scheme of the ~25.6 kb Xq28 deletion, showing CMC4, MTCP1, BRCC3 and FUNDC2, with coordinates, deletions and primers indicated. (C) IGV-browser showing Sashimi plots at CMC4 and BRCC3 from the index and controls, for RNA-seq of fibroblasts cultured with or without cyclohexamide (CHX). Also shown are WES data for the same region for index and unaffected parents, and schematic showing the expressed transcripts of CMC4 and BRCC3. The index has no DNA and RNA-seq reads mapping to CMC4 and exons 1-5 of BRCC3, indicating the presence of a maternally inherited hemizygous deletion encompassing CMC4, MTCP1 and BRCC3 (exons 1-5). (D) PCR validation of deletion. Shown are PCR products for the index (2x), mother, unrelated and negative control (blank). PCR was performed using primer A and a mixture of primers B and C (see panel B), giving rise to a 491 bp wild-type band and a 257 bp deletion-specific band. PCR validation confirmed the maternally inherited hg19: ChrX: 154286518_154312186del in the index.
case_images: CGE-107-341-g003.jpg
case_images: PMC11790519_01_CGE-107-341-g003.jpg
case_images: cge14650-fig-0002
case_images: RNA-seq on fibroblast-derived RNA revealed the significant downregulation of CMC4, MTCP1, BRCC3 and ACOT9 (Figure 2A), the latter being explained by a maternally inherited frameshift variant in ACOT9, a gene without the OMIM phenotype. Retrospective WES-data analysis revealed a maternally inherited, hemizygous Xq28 deletion of ~25.6 kb (hg19: ChrX:154286518_154312186del) (Figure 2C), which was PCR-validated (Figure 2D).