Identification of microduplications at Xp21.2 and Xq13.1 in neurodevelopmental disorders

Abstract

Background: Microduplications are a rare cause of disease in X-linked neurodevelopmental disorders but likely have been under reported due challenges in detection and interpretation. Methods: We performed exome sequencing and subsequent microarray analysis in two families with a neurodevelopmental disorder. Results: Here, we report on two families each with unique inherited microduplications at Xp21.2 and Xq13.1, respectively. In the first family, a 562.8-kb duplication at Xq13.1 covering DLG3, TEX11, SLC7A3, GDPD2, and part KIF4A was identified in a boy whose phenotype was characterized by delayed speech development, mild intellectual disability (ID), mild dysmorphic facial features, a heart defect, and neuropsychiatric symptoms. By interrogating all reported Xq13.1 duplications in individuals affected with a neurodevelopmental disorder, we provide evidence that this genomic region and particularly DLG3 might be sensitive to an increased dosage. In the second family with four affected males, we found a noncontinuous 223-and 204-kb duplication at Xp21.2, of which the first duplication covers exon 6 of IL1RAPL1. The phenotype of the male patients was characterized by delayed speech development, mild to moderate ID, strabismus, and neurobehavioral symptoms. The carrier daughter and her mother had learning difficulties. IL1RAPL1 shows nonrecurrent causal structural variation and is located at a common fragile site (FRAXC), prone to re-arrangement. Conclusion:In conclusion, we show that comprehensive clinical and genetic examination of microduplications on the X-chromosome can be helpful in undiagnosed cases of neurodevelopmental disease.

How many missed abortions are caused by embryonic chromosomal abnormalities and what are their risk factors?

“…Some of these factors are similar in two pregnancies in the same woman, which means that if a woman has two or more missed abortions, both partners need to have a more detailed pre-pregnancy examination before the next pregnancy. Moreover, although some microdeletions and microduplications of embryonic chromosomes have been reported to lead to missed abortion ( Cui et al, 2021 ; Familiari et al, 2021 ; Kokkonen et al, 2021 ; Baba et al, 2022 ; Yue et al, 2022 ), and the chromosome microduplication rate of the missed abortion group was higher than that of the normal abortion group in our cohort, there was no significant difference between the two groups.…”

“…Frontiers in Genetics frontiersin.org Kokkonen et al, 2021;Baba et al, 2022;Yue et al, 2022), and the chromosome microduplication rate of the missed abortion group was higher than that of the normal abortion group in our cohort, there was no significant difference between the two groups.…”

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

“…A plethora of computational CNV analysis software is freely available, both for GS (e.g., CNVnator [ 10 ] or LUMPY [ 11 ]) as well as ES or gene panel data (CoNIFER [ 12 ], ExomeDepth [ 13 ], and XHMM [ 14 ], among many others). Although the lack of a uniform coverage characteristic for ES and gene panels presents a challenge for computational CNV detection, necessitating a critical examination of the software calls and the validation of results by other methods, countless examples of cases solved with CNV detection software have been published (see, for example [ 9 , 15 ]). Some chromosomes and regions appear to be more CNV-rich and are implicated in developmental disorders more than others [ 16 , 17 , 18 ].…”

Unexpected Kif4a functions in adult regeneration encompass a dual role in neurons and in proliferative repair Schwann cells

“…The importance of KIF4A role in developing nervous systems is emphasized by the association of abnormal KIF4A expression with various neuropathologies, such as developmental delay, intellectual disability, hydrocephalus and brain anomalies (manifestations of the 'KIF4A-associated syndrome') 47 , and other human cognitive phenotypes, like Mental Retardation X-linked 100, a developmental disorder characterized by microcephaly, cortical malformations, abnormal higher mental functions, seizures, and poor speech [47][48][49] (www.malacards.org). KIF4A is also abnormally expressed in several cancers, including glioblastoma 50 , and its knockdown or overexpression can inhibit proliferation and migration of cancer cells.…”