A novel phenotype characterized by digital abnormalities, intellectual disability, and short stature in a Mexican family maps to Xp11.4–p11.21

Abstract

The family observed in this study included affected males and asymptomatic females. The patients shared specific digital abnormalities including postaxial polydactyly, cutaneous syndactyly, and brachydactyly. In addition, the patients exhibited mild-to-moderate intellectual disability and short stature coupled with microbrachycephaly, scoliosis, and cerebellar and renal hypoplasia. No chromosomal alterations or copy number variations were found in the index case. The genetic linkage analysis, which focused on the X chromosome, and the haplotype analysis detected a ~15.74 Mb candidate region located at Xp11.4-p11.21 with a LOD score of 4.8. Additionally, half of the mothers showed skewed X-inactivation, while the other mothers exhibited random inactivation patterns. The candidate region includes 28 protein-encoding genes that have not yet been implicated in human disorders. We speculate that the observed phenotype is compatible with a monogenic disorder in which the mutant gene plays a significant role during embryonic development. Based on the patients' clinical features, image studies, pedigree, chromosome location, and X-inactivation studies in the mothers, we propose that this family has a novel, specific syndrome with an X-linked recessive mode of inheritance.

Phenotypic severity in a family with MEND syndrome is directly associated with the accumulation of potentially functional variants of cholesterol homeostasis genes

“…This study represents the follow‐up of two previous works. The initial work (Barboza‐Cerda et al, ) was approved by the ethics committee (GN11‐001) of the Facultad de Medicina, Universidad Autónoma de Nuevo León, Mexico. The four mothers of the patients affected with MEND syndrome kindly signed informed consent forms for extraction of genomic DNA from blood.…”

“…In College of medical genetics annual clinical genetics meeting. Albuquerque, NM) and the remaining cases represented by members of three families (Barboza‐Cerda, Campos‐Acevedo, Rangel, Martínez‐de‐Villarreal, & Déctor, ; Furtado et al, ; Hartill et al, ). Overall, mutations in EBP appear to give rise to a continuous spectrum of phenotypes likely related to variations in total Δ8, Δ7 sterol isomerase activity and zygosity (Barboza‐Cerda, Wong, Martínez‐de‐Villarreal, Zhang, & Déctor, ).…”

“…Sporadic cases of MEND syndrome with the more severe phenotype result in death in early childhood, but familial cases are associated with the longest survival among patients with MEND syndrome; these cases show subtle but significant phenotypic differences despite sharing the same mutation. In one (Barboza‐Cerda et al, ) of the two families with MEND syndrome exhibiting the largest number (4) of patients, differences in the degree of intellectual disability and expressivity of digital abnormalities were observed; in the other family (Hartill et al, ), differences in the presentation of behavioral disturbances and a scarcity of structural anomalies were reported.…”

A novel EBP c.224T>A mutation supports the existence of a male‐specific disorder independent of CDPX2

“…Recently, we described a novel phenotype in a Mexican family that is primarily characterized by specific digital abnormalities, intellectual disability and short stature coupled with microbrachycephaly, scoliosis and cerebellar and renal hypoplasia [Barboza‐Cerda et al, ]. The digital abnormalities include bilateral brachydactyly of fingers 2, 4, and 5; bilateral camptodactyly and bilateral syndactyly of fingers 4–5; bilateral cutaneous syndactyly of toes 2–3; and right or left postaxial polydactyly of the feet.…”

“…We speculated that this phenotype could be due to a point mutation in a single gene whose temporal and spatial expression is confined to certain tissues during embryonic development. Through linkage analysis, we further proposed that the candidate gene must be among the 28 protein‐encoding genes in the Xp11.4–p11.21 candidate region [Barboza‐Cerda et al, ].…”