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Segregation of a nonsense variant in TP63 in a five-generation family with non-syndromic cleft lip and palate

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction
Tumor protein p63 (TP63) gene codes for a transcription factor which plays a key role in limb, craniofacial, and epithelial development. TP63-related disorders are autosomal dominant and encompass a wide range of phenotypes, including ectodermal dysplasia, cleft lip/palate, split-hand/foot malformation, mammary hypoplasia, hypopigmentation and ankyloblepharon ectodermal dysplasia. Missense variants resulting in a dominant-negative or gain-of-function effect are the predominant cause of TP63-associated syndromes, whereas few rare loss-of-function variants have been reported to cause non-syndromic orofacial clefting. About one-third of individuals diagnosed with a TP63-related disorder inherit a pathogenic variant from a parent. Incomplete penetrance and intrafamilial variability are seen for TP63 variants; however, penetrance rate remains unknown. This study provides a comprehensive evaluation of a large five-generation family with cleft lip and palate in multiple members with the segregation of a nonsense variant in TP63.

Case Presentation
The male infant was born at 39w4d with a left unilateral cleft lip and cleft palate, which was diagnosed prenatally, to a G2P2002 woman via spontaneous vaginal delivery. The pregnancy was otherwise uncomplicated with no in utero exposures. He had a history of failed newborn hearing screen with a follow up secondary to bilateral conductive hearing loss. There was initial poor weight gain, feeding difficulties which resolved. The infant had no ocular, skin, or limb anomalies. The family history was significant for cleft lip and palate in the maternal grandmother, great-grand aunt, first cousin twice removed and a second cousin suggestive of underlying genetic etiology for the cleft lip with cleft palate.

Diagnostic Workup
Genetic testing was performed on the proband at 5 m.o. utilizing our in-house Cleft and Craniofacial Gene Panel, which is a whole exome slice of 288 genes. Trio analysis was included in this test with parental samples performed by targeted sanger sequencing to evaluate the inheritance of variants.

Outcome and Follow-Up
A maternally inherited heterozygous stop gain variant, c.1177C>T (p.Arg393Ter), located in the oligomerization domain of the TP63 gene was identified and classified as likely pathogenic based on the ACMG/AMP variant guidelines. Targeted analysis of several maternal relatives indicates segregation of the variant with the maternal grandmother, who was born with cleft lip and palate, as well as the mother, aunt, and uncle, who did not have cleft lip or cleft palate, consistent with incomplete penetrance. Notably, unaffected individuals who are positive for the variant report variable mild ectodermal abnormalities, including hypohidrosis, enamel hypoplasia, and an increased incidence of dental caries. Testing of additional family members from this five-generation pedigree is in progress.

Conclusion
The nonsense variant in TP63 was identified as the cause of cleft lip and palate in this proband. This finding provides additional evidence that variants within the oligomerization domain and/or with a potential loss-of-function effect are a cause of non-syndromic cleft lip with/without palate (nsCLP). This variant was identified in additional maternal family members, who have not had genetic evaluation for nsCLP or ectodermal dysplasia in the past and will benefit from genetic counseling for reproductive planning. To our knowledge, this five-generation family represents the largest cohort study to date with TP63-related nsCLP. Testing of additional affected and unaffected relatives from this large family will provide insights into the penetrance rate of TP63 variants. Additionally, the presence of mild ectodermal anomalies in individuals with the variant raises the possibility that orofacial clefting may not be an entirely isolated feature, suggesting a broader phenotypic spectrum of ‘non-syndromic’ cleft lip and palate.

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