A homozygous 237-kb deletion at 1p31 identified as the locus for midline cleft of the upper and lower lip in a consanguineous family

Abstract

Orofacial clefts are congenital defects that vary widely in type and severity, and can occur in isolation or in association with a variety of other defects. Herein, we describe a consanguineous family afflicted with a unique form of orofacial clefting manifesting as a facial midline defect that also involves mandibular and maxillary structures. All four affected sibs had median clefts of the upper and lower lips, tooth misalignment, and poor oral hygiene. Linkage analysis of 17 family members identified a 15.3-Mb pair recessive locus at 1p31 with a LOD score of 3.63. To the best of our knowledge, this is, to date, the first locus reported for facial midline clefting and the first recessive locus for an isolated orofacial defect. The locus harboured a novel intergenic deletion of 273 164 bp, for which all fully affected sibs were homozygous. We did not note any potentially pathogenic gene variant at the 1p31 locus via exome-sequencing analysis. The identified deletion could be harbouring a regulatory element for the gene associated with the orofacial defect. The best candidate for the putative target gene is LHX8, located 49 149 bp upstream of the deletion. The gene is known to be associated with facial development in several animals. Four other family members had a subclinical phenotype -a simple notch in the lower lip or an increase in the interdental distance between the lower incisors -indicative of very low-level expression of the trait.

Discovery of candidate genes for nonsyndromic cleft lip palate through genome-wide linkage analysis of large extended families in the Malay population

“…Several studies have documented their findings regarding 1p chromosomal region. A novel homozygous intergenic deletion of 237-kb at 1p31 was reported in four affected siblings of consanguineous marriage and 1p31 is an autosomal recessive locus [ 14 ]. It was previously reported that locus 1p34 has a positive linkage among families with a history of Van der Woude syndrome (VWS) that brought it to the interest because it closely resembles the phenotype of NSCLP [ 25 ].…”

“…Linkage studies have revealed several candidate regions studied in different populations. A consanguineous family with 17 members has reported to have homozygous 237-kb deletion at locus 1p31 among the family members that cause cleft lip [ 14 ]. Three regions of chromosome 1; 1p36, 1q21 and 1q32-42.3, which 1p36 regions had positive scores by parametric linkage approach and pairwise analysis found susceptibility gene on 1q21 and 1q32-42.3 regions in 38 families of NSCLP from Northeastern Italy [ 15 ].…”

Partial Deletion of Chromosome 1p31.1 Including only the Neuronal Growth Regulator 1 Gene in Two Siblings

“…Psychiatric diagnoses included attention deficit a Adapted from references. [1][2][3][4][5][6][7][8][9] Note: AE, may or may not have this clinical feature. hyperactivity disorder (ADHD), sensory integration dysfunction, and speech articulation difficulty.…”

“…Interstitial deletions of chromosome 1p31 have been reported in at least 10 individuals and phenotypic characteristics summarized by Mircher et al 1 Clinical findings included intellectual disability, hypertonia, failure to thrive, microcephaly, broad nasal tip, tendency for an open mouth, micrognathia, short neck, fifth finger clinodactyly, and tapering fingers. Additional features described more recently included short stature, obesity, facial asymmetry, hypodontia, 2 ventriculomegaly, hypogenesis of the corpus callosum, abnormal external genitalia, 3 prominent supraorbital ridges, pectus excavatum, high-arched palate, 4 strabismus, midline cleft of the upper and lower lip, and autism spectrum disorder 5,6 (►Table 1). Neuropsychiatric or behavioral phenotypes for chromosome 1p31 deletion have been poorly characterized to date beyond autism spectrum disorder and intellectual disability.…”

Two novel genes TOX3 and COL21A1 in large extended Malay families with nonsyndromic cleft lip and/or palate

“…Linkage studies have successfully revealed several different candidate loci studied in different populations. For example, a consanguineous family with 17 members was reported to have a homozygous 237‐kb deletion at locus 1p31 among the family members that cause cleft lip (Yıldırım, Kerem, Köroğlu, & Tolun, ). There are a lot of studies that revealed the causative genes to nonsyndromic cleft lip palate (NSCLP) formation such as TGF family, FGF family, cleft lip, and palate have been associated transmembrane protein 1 ( CLPTM1 ), special AT‐rich sequence‐binding protein 2 ( SATB2 ), and small ubiquitin‐like modifier 1 ( SUMO1 ) and IRF6 (Carter et al, ; Nie, Luukko, & Kettunen, ; Pauws & Stanier, ; Scapoli et al, ).…”