The<unk>  at<unk> .2, especially the<unk> .22-11.23 region is syndromic and is implicated in X-linked mental retardation. The chromosomal<unk>  can be de novo or familial. Familial carriers of small<unk>  (<1 Mb) show X-linked recessive inheritance. All other affected individuals with larger<unk>  present dominant expression and comparable clinical phenotypes irrespective of sex,<unk>  size, and X-inactivation pattern.<unk> .22 comprises approximately 5 Mb of DNA (chrX:49,800,001–54,800,000, hg19). A number of pathogenic deletions and<unk> s involving<unk> .22 have been described in individuals with developmental delay, intellectual disability and/or autism. These phenotypes have been attributed to changes in the copy number of several genes including HUWE1, KDM5C, IQSEC2, TSPYL2, SHROOM4, PHF8 and FAM120C. HUWE1 The HECT, UBA and WWE domain-containing protein 1 (HUWE1) is a HECT family ubiquitin ligase located on the X chromosome at<unk> .22 with growing genetic links to cancer and intellectual disability. Expression of the HUWE1 gene is found in several mouse tissues including cortex, hippocampus, tongue, eye, kidney, liver, adrenal gland, and fibroblasts. Increased copies of HUWE1 are associated with non-syndromic intellectual disability. Missense mutations in HUWE1 occur in multiple families with intellectual disability, including families with Juberg-Marsidi-Brooks syndrome. Patients with missense mutations in HUWE1 share clinical features with patients with a<unk>  of HUWE1. This suggests both increased and decreased HUWE1 function could be associated with intellectual disability, but evidence from an in vivo model system supporting or refuting this possibility remains absent. KDM5C KDM5C (Lysine-Specific Demethylase 5C) also known as jumonji, A/T-rich interactive domain 1C (JARID1C) is located on the X chromosome at<unk> .22-p11.21. The gene encodes a 1560 amino-acid protein that belongs to the JARID1 subfamily of Arid DNA-binding proteins. The protein possesses H3K4me3-specific demethylase activity and is shown to function as a transcriptional repressor through the RE-1-silencing transcription factor (REST) complex. The mutations in KDM5C cause Claes-Jensen type syndromic X-linked Intellectual Disability characterized by moderate-to-severe ID, speech abnormalities and other clinical findings such as seizures and aggressive behavior in some individuals. There is also a report of a mutation in a patient with autism spectrum disorder. A study showed that Kdm5c-knockout mice exhibit adaptive and cognitive abnormalities similar to those in human X-linked intellectual disability and concluded that histone methylation dynamics sculpt the neuronal network. IQSEC2 IQ motif and Sec7 domain 2 (IQSEC2), also known as BRAG1 or IQ-ARFGEF, is located on the X chromosome at<unk> .22 and encodes guanine nucleotide exchange factor for the ARF family of GTP-binding proteins (ARFGEF). It is expressed in the neurons and is involved in cytoskeletal organization, dendritic spine morphology, and excitatory synaptic organization. Mutations in IQSEC2 are widely associated in cases of X-linked non-syndromic mental retardation, with some carrier females reported with learning disabilities. This gene is known to play a significant role in the maintenance of homeostasis within the neural environment of the human brain. A change of guanine nucleotide exchange factor activity may influence the regulation of actin cytoskeleton organization and neuronal development in the brain by reduced activation of the ARF6 substrate or a defect in the GTP-binding activity. Two intragenic<unk> s predicted to cause termination mutations on the X-chromosome involving IQSEC2 were identified in two de novo cases, and one nonsense mutation was described in three additional male patients presenting severe intellectual disability and additional clinical features including neonatal hypotonia, delayed motor skills, seizures, strabismus, autistic-like behavior, stereotypic midline hand movements, microcephaly, little-to-no walking, little-to-no language skills, significant behavioral issues, and mildly abnormal facial features. A novel de novo mutation in the IQSEC2 gene identified through diagnostic exome sequencing showed significant developmental delay, seizures, hypotonia, vision impairments, plagiocephaly, autistic-like features, absent language skills, and abnormal MRI findings. IQSEC2 gene plays a larger role in the cause of X-linked cognitive impairment than previously thought. Additional consideration is warranted with regards to the syndromic nature of its phenotypic association. TSPYL2 Testis-Specific Protein Y-encoded (TSPY) Like 2 (TSPYL2) codes for a member of the TSPY-like/SET/nucleosome assembly protein-1 superfamily and is located on the X chromosome at<unk> .22. The encoded protein is localized to the nucleolus where it functions in chromatin remodeling and as an inhibitor of cell-cycle progression. Consistent with a possible role for Tspyl2 pathways in neurodevelopment,<unk> .2 microduplication incorporating the TSPYL2 locus has been reported in male patients with Attention Deficit Hyperactivity Disorder. SHROOM4 Shroom Family Member 4 (SHROOM4), also known as KIAA1202, encodes a member of the APX/Shroom family, which contains an N-terminal PDZ domain and a C-terminal ASD2 motif. It is located on the X chromosome at<unk> .22 and is mainly associated with the Stocco dos Santos X-linked mental retardation syndrome characterized by cognitive disabilities. The encoded protein may play a role in cytoskeletal architecture. Symptoms of SHROOM4 gene mutations in the original family described by Stocco dos Santos include severe intellectual disability, bilateral congenital hip luxation and short stature. The SHROOM4 gene was also found to be disrupted in two unrelated females with mild to moderate intellectual disabilities. Other features included delayed or no speech, seizures, kyphosis and hyperactivity. Carrier females displayed seizures and depression. No mutations in SHROOM4 were identified in more than 1000 control X chromosomes.
Xp11.2 duplication
Chromosome 2q deletion
2q37 monosomy
Chromosome 15q partial deletion
Partial monosomy 13q
Distal trisomy 10q
Tetrasomy 18p
Chromosome 15q trisomy