7q21.3 Deletion involving enhancer sequences within the gene DYNC1I1 presents with intellectual disability and split hand-split foot malformation with decreased penetrance

Abstract

Split hand-split food malformation (SHFM) is a congenital defect of limb development that involves the central rays of the autopod and presents with median clefts of the hands and feet. It often includes syndactyly and aplasia/hypoplasia of the phalanges. SHFM is a genetic condition with high genetic heterogeneity, with at least 6 associated chromosomal loci. A locus in chromosomal region 7q21.3, associated with SHFM is referred to as SHFM1. Genes considered to be associated with SHFM1 are DLX5 and DLX6. These two genes participate in the Wnt pathway that has a role in limb development. The gene DYNC1I1, located proximally (centromeric) to the SHFM1 locus was recently reported to include enhancer sequences involved in limb development in its exons 15 and 17. These sequences were shown to cis-regulate the function of the adjacent SHFM associated genes. We report a family, in which the father and three of his sons carry an approximately 1 Mb deletion in this chromosomal region, arr[hg19]7q21.3(94,769,383-95,801,045)x1. The deleted region is located proximally (centromerically) adjacent to the SHFM region at 7q21.3. It does not include the SHFM candidate genes DLX5 and DLX6, but includes the enhancer sequences within DYNC111 and six other genes centromeric to DYNC1I1. All deletion carriers have various degrees of intellectual disability while two of them have SHFM. This family is the eighth reported family where a chromosome 7q21.3 deletion co-segregating with SHFM involves the enhancer regions within gene DYNC111, but does not involve the genes DLX5 and DLX 6. This is also the third family where decreased penetrance of enhancer-associated SHFM is demonstrated. Intellectual disability was not observed in the previously reported families and may be associated with deficiency of one or more of the 6 genes included in the reported deletion centromeric to DYNC1I1.

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups

“…62 74 One limitation to the current study is the lack of adherence and dietary information which could affect tacrolimus trough concentrations, however, when nonadherence was suspected, the trough concentration around that time was excluded. 62 74 One limitation to the current study is the lack of adherence and dietary information which could affect tacrolimus trough concentrations, however, when nonadherence was suspected, the trough concentration around that time was excluded.…”

“…involved in limb development and its association with metabolism is uncertain. 74 One limitation to the current study is the lack of adherence and dietary information which could affect tacrolimus trough concentrations, however, when nonadherence was suspected, the trough concentration around that time was excluded. Because of the large number of variants studied, the power for discovery is low and these variants must be validated in other populations.…”

A novel description of a syndrome consisting of 7q21.3 deletion including DYNC1I1 with preserved DLX5/6 without ectrodactyly: a case report

“…These include distal-less homeobox 5 ( DLX5 ; MIM 600028) , distal-less homeobox 6 (DLX6 ; MIM 600030), deleted in split hand/split foot malformation 1 region ( SHFM1 ; MIM 601285), and dynein cytoplasmic 1 intermediate chain 1 ( DYNC1I1 ; MIM 603772) through its exonic enhancers ( eExons ) 15 and 17 . So far, there are reports of eight families with deletion of DYNC1I1 and preserved DLX5/6 associated with ectrodactyly, the main manifestation of the SHFM1 syndrome [ 3 ]. We report a case that involves a deletion of 3 Mb in chromosome 7q21.3 region including DYNC1I1 with preserved DLX5/6 without ectrodactyly accompanied by craniofacial dysmorphology, personality disorder, hearing loss, musculoskeletal manifestations, bilateral inguinal herniae, and mitral valve prolapse.…”

A Novel Heterozygous Intragenic Sequence Variant in DLX6 Probably Underlies First Case of Autosomal Dominant Split-Hand/Foot Malformation Type 1

“…Split-hand/foot malformation-1 (SHFM1) is caused by chromosomal aberrations such as deletions, inversions, translocations, and duplications in a region in chromosome 7q21 encompassing the genes DLX5 , DLX6 and exonic enhancers of DYNC1I1 [Wieland et al, 2004;van Silfhout et al, 2009;Velinov et al, 2012;Delgado and Velinov, 2015]. Intragenic mutations in the DLX5 gene have been reported in families segregating SHFM in autosomal dominant fashion.…”