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. 2022 Nov;86(6):291-296.
doi: 10.1111/ahg.12462. Epub 2022 Aug 30.

A splice site variant in TCTN3 underlies an atypical form of orofaciodigital syndrome IV

Shabir Hussain  1 , Shoaib Nawaz  2 , Hammal Khan  1   3 , Anushree Acharya  4 , Isabelle Schrauwen  4 , Wasim Ahmad  1 , Suzanne M Leal  4   5
Affiliations

A splice site variant in TCTN3 underlies an atypical form of orofaciodigital syndrome IV

Shabir Hussain et al. Ann Hum Genet. 2022 Nov.

Abstract

Orofaciodigital syndrome (OFD) is clinically heterogeneous and is characterized by abnormalities in the oral cavity, facial features, digits, and central nervous system. At least 18 subtypes of the condition have been described in the literature. OFD is caused by variants in several genes with overlapping phenotypes. We studied a consanguineous Pakistani family with two affected siblings with an atypical form of OFD type 4 (OFD4). In addition to the typical features of OFD4 that include limb defects and growth retardation, the siblings displayed rare features of scaphocephaly and seizures. Exome sequencing analysis revealed a novel homozygous splice site variant c.257-1G>A in TCTN3 that segregated with disease. This homozygous splice site variant in TCTN3 is most likely the underlying cause of the atypical form of OFD4 observed in this family. Our results contribute to the phenotypic spectrum of TCTN3 associated ciliopathies and will facilitate better clinical diagnosis.

Keywords: TCTN3; orofaciodigital syndrome; scaphocephaly; seizures.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Genetic and clinical data. Pedigree drawing for consanguineous Pakistani pedigree BD432 segregating OFD4 (Panel a). Two affected individuals (IV‐1 and IV‐2) were homozygous for the TCTN3 variant [c.257‐1G>A]. Three individuals (III‐1, III‐2, and IV‐4) were carriers and IV‐3 was homozygous wildtype. Variant genotypes are shown under each individual with an available DNA sample. Pictures and x‐rays for affected individual IV‐1 (Panel b). Pictures showing scaphocephaly (i‐ii) and metatarsus adductus (iii). X‐rays of affected individual IV‐1 displaying scaphocephaly and beaten copper skull appearance (iv‐v), smaller cuneiform bone of right foot (vi), short carpal bones in the right hand and bowed radii (vii) and hypoplastic greater trochanter of right femur (viii). Sanger sequencing chromatograms showing splice site variant [c.257‐1G>A] for a wildtype normal (IV‐3), a heterozygous carrier (III‐1) and a homozygous affected (IV‐2) individual (Panel c)
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