A patient with a mild holoprosencephaly spectrum phenotype and heterotaxy and a 1.3 Mb deletion encompassing GLI2

Abstract

Loss-of-function mutations of GLI2 are associated with features at the mild end of the holoprosencephaly spectrum, including abnormal pituitary gland formation and/or function, and craniofacial abnormalities. In addition patients may have branchial arch anomalies and polydactyly. Large, microscopically visible, interstitial deletions spanning 2q14.2 have been reported in patients with multiple congenital anomalies and intellectual disability. We report here on a patient with a mild holoprosencephaly spectrum phenotype (bilateral cleft lip and palate and abnormal pituitary gland formation with panhypopituitarism) and normal psychomotor development, who was found to carry a 1.3 Mb submicroscopic heterozygous deletion in 2q14.2, encompassing the GLI2 gene. We review the genotype and phenotype of previously published probands with GLI2 aberrations. Our findings confirm the association of haploinsufficiency of GLI2 and mild HPE spectrum features. Consistent with prior reports, we observed incomplete penetrance of the deletion in the family, illustrating the multifactorial etiology of holoprosencephaly spectrum features. In addition to the holoprosencephaly spectrum features, the proband had heterotaxy of the abdominal organs. Mutations in the known heterotaxy genes (NODAL, ZIC3 and CFC1) were excluded. The deletion contains five genes, in addition to GLI2, including the EPB4.1l5 gene. Based on findings in Epb4.1l5 mutant mice we hypothesize that Epb4.1l5 is a candidate gene for the heterotaxy observed in the proband.

Three GLI2 mutations combined potentially underlie non‐syndromic cleft lip with or without cleft palate in a Chinese pedigree

“…Misregulation of the GLI2 (OMIM: 165230) gene could therefore lead to unfavorable developmental and pathological consequences (Hui & Angers, ). Mutations in GLI2 have been identified in patients with orofacial cleft (Bertolacini, Ribeirobicudo, Petrin, Richiericosta, & Murray, ; Mo et al, ; Simioni, Araujo, Monlleo, Maurer‐Morelli, & Gil‐Da‐Silva‐Lopes, ; Vieira et al, ), holoprosencephaly (Bear et al, ; Kevelam et al, ), and pituitary anomalies (Roessler et al, , ). Some variants of GLI2 have been detected in patients who present with cleft lip/palate by Sanger sequencing and are not in unrelated controls without orofacial cleft (Simioni et al, ).…”

Human Malformation Syndromes of Defective <b><i>GLI</i></b>: Opposite Phenotypes of 2q14.2 (<b><i>GLI2</i></b>) and 7p14.2 (<b><i>GLI3</i></b>) Microdeletions and a GLIA/R Balance Model

“…In fact, these 2 disorders belong to a continuous phenotypic spectrum, with the relatively mild forms referred to as CJS and severe cases known as HPE9 ( Table 1 ). Today, many case reports and reviews of human GLI2 defects have been made [Kevelam et al, 2012;Greally et al, 2014;Arnhold et al, 2015], and the actual spectrum of the phenotype of this syndrome has been clarified (online suppl. Table 1; see www.karger.com/doi/10.1159/000485227).…”

Sonic Hedgehog mutations are not a common cause of congenital hypopituitarism in the absence of complex midline cerebral defects

“…37 In addition, a case report on a patient with CPHD, cleft palate and heterotaxy used MLPA to confirm a whole GLI2 deletion first identified by array comparative genome hybridization. 38 In patients with SOD, the MLPA analysis did not detect GLI2 CNV. However, among these patients, we identified two novel GLI2 missense variants.…”

“…One previous study identified one patient with a heterozygous LHX4 microdeletion among 71 patients with CPHD that were examined for CNV by MLPA in POU1F1 , PROP1 , HESX1 , LHX3 , LHX4 and SOX3 genes . In addition, a case report on a patient with CPHD, cleft palate and heterotaxy used MLPA to confirm a whole GLI2 deletion first identified by array comparative genome hybridization …”