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

Abstract

Split-hand and foot malformation (SHFM; MIM 183600) is a rare human genetic limb malformation. It is characterized by missing digital rays in the hands and feet. SHFMs vary in severity from mild abnormalities affecting a single limb to acute malformations involving all 4 limbs. It is inherited, as part of both a syndromic and nonsyndromic disorder, in an autosomal recessive, autosomal dominant, and X-linked patterns. So far, 9 loci of hand and foot malformation have been mapped on human chromosomes. The present study describes a family with 2 affected individuals segregating SHFM in an autosomal dominant fashion. Sanger sequencing of the genes involved in SHFM was performed to identify the disease-causing variant. Sequence analysis revealed the first heterozygous missense variant (c.632T>A, p.Val211Glu) in the distal-less homeobox 6 (DLX6) gene, located in chromosome 7q21, causing SHFM in the present family. This study supports the evidence of DLX6 as an SHFM-causing gene.

First direct evidence of involvement of a homozygous loss‐of‐function variant in the EPS15L1 gene underlying split‐hand/split‐foot malformation

“…Data presented in these 3 reports and identification of the frameshift mutation (p.Ser137Alafs*19) in the family, presented here, supported the involvement of the EPS15L1 gene on chromosome 19p13.3‐p12 in causing SHFM phenotype. It is pertinent to report here that associated features reported with SHFM1, SHFM5, and SHFM6 such as polydactyly, cardiovascular anomalies, deafness, and nail clubbing were not observed in the affected individuals of our family.…”

“…Karyotype analysis was performed on peripheral blood lymphocytes collected from the proband (IV‐2) using the G‐banding technique …”

“…This included SHFM1 on chromosome 7q21 (MIM 183600), SHFM2 on Xq32 (MIM 313350), SHFM3 on 10q24 (MIM 246560), SHFM4 on 3q27 (MIM 605289), SHFM5 on 2q31 (MIM 606708), SHFM6 on 12q13.11‐q13 (MIM 183600), and a chromosomal region 8q21.11‐q22.3 . For these 7 loci, 5 genes including DLX5 (MIM 600028) and DLX6 for SHFM1, TP63 (MIM 603273) for SHFM4, WNT10B (MIM 601906) for SHFM6 and ZAK (MIM 616890) for split‐foot malformation with mesoaxial polydactyly have been identified. Three other types of SHFM associated with long‐bone deficiency (SHFLD), have been mapped.…”

Genetic regulatory pathways of split‐hand/foot malformation

“…SHFM has been reported to be associated with ectrodactyly‐ectodermal dysplasia‐clefting syndrome (EEC; MIM #129900), brachydactyly‐ectrodactyly with fibular aplasia or hypoplasia (MIM #113310), autosomal recessive DLX5 ‐associated SHFM, autosomal dominant DLX5 ‐associated SHFM, autosomal dominant DLX6 ‐associated SHFM, FGFR1 ‐associated congenital hypogonadotropic hypogonadism with SHFM (MIM #147950), BHLHA9 ‐associated SHFM with long‐bone deficiency (SHFMLD: MIM #119100), and autosomal recessive WNT10B ‐associated SHFM (SHFM6; MIM #225300) . A patient with Kabuki syndrome with SHFM has been reported, but molecular testing was not performed .…”

Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation

“… Shamseldin et al (2012) reported a mutation in the gene DLX5 responsible for the SHFM-1 phenotype in a consanguineous family. We reported intragenic variants in the DLX5 and DLX6 genes that caused the SHFM-1 phenotype in two different families ( Ullah et al , 2016a , b ). Goodman et al (2002) proposed that SHFM-5 and other digit defects may be caused by haploinsufficiency of genes ( EVX2 , DLX1 , DLX2 ) located at the 5′ end of the HOXD cluster.…”