Confirmation and expansion of the phenotype of the TCEAL1-related neurodevelopmental disorder

Abstract

Numerous contiguous gene deletion syndromes causing neurodevelopmental disorders have previously been defined using cytogenetics for which only in the current genomic era the disease-causing genes have become elucidated. One such example is deletion at Xq22.2, previously associated with a neurodevelopmental disorder which has more recently been found to be caused by de novo loss-of-function variants in TCEAL1. So far, a single study reported six unrelated individuals with this monogenetic disorder, presenting with syndromic features including developmental delay especially affecting expressive speech, intellectual disability, autistic-like behaviors, hypotonia, gait abnormalities and mild facial dysmorphism, in addition to ocular, gastrointestinal, and immunologic abnormalities. Here we report on four previously undescribed individuals, including two adults, with de novo truncating variants in TCEAL1, identified through trio exome or genome sequencing, further delineating the phenotype of the TCEAL1-related disorder. Whereas overall we identify similar features compared to the original report, we also highlight features in our adult individuals including hyperphagia, obesity, and endocrine abnormalities including hyperinsulinemia, hyperandrogenemia, and polycystic ovarian syndrome. X chromosome inactivation and RNA-seq studies further provide functional insights in the molecular mechanisms. Together this report expands the phenotypic and molecular spectrum of the TCEAL1-related disorder which will be useful for counseling of newly identified individuals and their families.

Fig. 1. Clinical phenotypes of individuals with TCEAL1 variants.

A Family pedigrees of affected individuals, with TCEAL1 variant indicated. Affected individuals harboring TCEAL1 variants are indicated with black filled symbols, numbered, and highlighted by the arrows. B Clinical photographs of affected individuals. Individual 1 has a coarse face, with straight eyebrows, deep-set and elongated palpebral fissures, prominent nasal tip, short philtrum, pointy chin, and a high anterior hairline. Hands with short appearing distal phalanges and mild bilateral fifth digit clinodactyly. Feet with hallux valgus. Individual 2 has deep-set and long palpebral fissures with mild downslant, a broad nasal bridge, thin and slightly tented upper lip vermilion, small ears, hands with short appearing distal phalanges and flat feet. Individual 3 has a triangular face, with a high and wide forehead, frontal bossing, hypertelorism, downslanting palpebral fissures, hypoplasia of the alae nasae, short philtrum and thin upper and lower lip vermilion. Feet are flat and in valgus position. Individual 4 has a high anterior hairline and frontal bossing, deep-set and elongated palpebral fissures with mild ptosis, bulbous nose with a flattened nasal bridge and round nasal tip, hypertelorism, micrognathia, brachydactyly and low-set ears. C T2 weighted brain MRI images from Individual 2 showing bilateral frontal focal subcortical heterotopia (indicated with arrow heads). D Schematic representation of the TCEAL1 protein (UniProt: Q15170, 159 aa). Three domains are indicated: the arginine/serine (RS) rich domain (green), the zinc finger-like (ZnF-L) domain (brown), and the helix-turn-helix (HTH) domain (grey). Variants reported in this paper (above), and the previously reported de novo variants in TCEAL1 [5] (below) are indicated. In red are variants found in females and in blue are variants found in males. Red dotted line represents the previously reported ~14 kb TCEAL1 deletion.

Fig. 2. X chromosome inactivation and RNA-seq studies.

A Analysis of X-inactivation for individual 1 (performed twice in two different blood derived DNA samples) and individual 2, performed as previously described [10, 12]. In the undigested samples, PCR analysis visualizes the two alleles of a polymorphic short tandem repeat at the human androgen receptor locus (HUMARA). Upon digestion with the methylation sensitive restriction enzymes Hpall and Hhal, only the methylated allele on the inactive X chromosome is amplified, and the ratio between results from digested and undigested samples is used to calculate the ratio of X inactivation skewing. XCIP = X chromosome inactivation pattern; −(Hpall/Hhal) = undigested DNA; +(HpaII/Hhal) = digested DNA. B IGV genome browser view of exome sequencing (on blood derived DNA) from unaffected mother (upper track) and her son (individual 4, middle track) and RNA sequencing of fibroblasts derived from individual 4 (lower track). Results confirm the de novo origin of the NM_004780.3 (TCEAL1):c.311_314del, p.(Glu104GlyfsTer18) variant and its stable expression at RNA level with a z-score of 1.773 in fibroblasts without evidence of nonsense-mediated decay.