Pituitary stalk interruption syndrome broadens the clinical spectrum of the <scp>TTC26</scp> ciliopathy

David, Odeya; Eskin‐Schwartz, Marina; Ling, Galina; Dolgin, Vadim; Kristal, Eyal; Benkowitz, Ela; Osyntsov, Lidia; Gradstein, Libe; Birk, Ohad S.; Loewenthal, Neta; Yerushalmi, Baruch

doi:10.1111/cge.13805

Cited by 10 publications

(8 citation statements)

References 23 publications

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“…Features such as developmental delay, dysmorphic facial features, liver abnormalities, and cardiovascular disorders were similar to those reported previously [Shaheen et al, 2020]. More recently, pituitary stalk interruption syndrome has been reported in patients [David et al, 2020]. Pituitary hypoplasia was also reported in our patient; however, diabetes insipidus was not reported previously, and hydrocephalus has been reported in 1 of the 7 ciliopathies cases so far.…”

Section: Wgs and Sanger Sequencingsupporting

confidence: 90%

“…Using WES, Shaheen et al [2020] identified 3 homozygous variants (c.695A>G; c.4-1G>C; c.1238C>T) in the TTC26 gene of 7 different families in Saudi. Recently, David et al [2020] identified a homozygous missense variant, c.695A>G (p.Asn232Ser), in 2 Israeli families.…”

Section: Discussionmentioning

confidence: 99%

“…1e). Shaheen et al [2020] and David et al [2020] described individuals with severe ciliopathy phenotypes, including neonatal cholestasis, in different Saudi and Israeli families. In the present study, we investigated a Saudi proband with severe clinical presentations such as optic atrophy, cholestasis, knee hyperextensibility, hydrocephalus, atrioventricular septal defect , pituitary hypoplasia, and developmental delay.…”

Section: Wgs and Sanger Sequencingmentioning

confidence: 99%

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Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Alfadhel¹,

Umair²,

Almuzzaini³

et al. 2021

Mol Syndromol

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Ciliopathies constitute heterogeneous disorders that result from mutations in ciliary proteins. These proteins play an important role in the development of organs, physiology, and signaling pathways, and sequence variations in the genes encoding these proteins are associated with multisystem disorders. In this study, we describe a severe ciliopathy disorder that segregates in an autosomal recessive manner in a nonconsanguineous Saudi family. The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Whole-genome sequencing and Sanger sequencing revealed a homozygous splice site variant (c.4–1G>C; NM_024926.3) in the tetratricopeptide repeat domain 26 (TTC26) gene located in chromosome 7q34, which cosegregated perfectly with the disease phenotype. qRT-PCR revealed a substantial decrease in the expression of the TTC26 gene as compared to the normal control, suggesting the pathogenicity of the identified variant. This report further strengthens the evidence that homozygous variants in the TTC26 gene cause severe ciliopathies with diverse phenotypes. We named this newly characterized condition as BRENS syndrome, which stands for biliary, renal, neurological, and skeletal features.

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Section: Wgs and Sanger Sequencingsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Wgs and Sanger Sequencingmentioning

confidence: 99%

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Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Alfadhel¹,

Umair²,

Almuzzaini³

et al. 2021

Mol Syndromol

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“…6 The four Israeli patients that were later reported displayed similar clinical features with additional pituitary gland and ocular findings, however, data on additional patients are needed to determine whether this represent a true difference between the populations. 7 On January 1, 2021, 1243 variants were cataloged in the INGD among Muslim Israeli Arabs 47 out of which were also reported in Saudi Arabia (3.8%). In many cases these were founder/assumed founder variants, but there were exceptions in both populations.…”

Section: Discussionmentioning

confidence: 99%

Forty‐seven pathogenic variants causing autosomal recessive disorders are shared by Israeli and Saudi Arabian Arabs

Zlotogora¹

2021

Clinical Genetics

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Several autosomal recessive disorders that are found among Arabs in Israel were also reported in Saudi Arabia. In a sytematic review of all the variants responsible for autosomal recessive disorders among Muslim Arabs Israel and in Saudi Arabia, 47 shared variants were found, many being known founder variants in both populations. Among the 21 shared variants that were reported among Bedouins 14 were founder variants representing 14% founder/assumed founder variants known in the Bedouins. Many of the common variants are ancient having a Bedouin origin probably linked to the migration from the Saudi Peninsula. It is probable that a similar phenomenon occurred along the route of the Bedouin migrations and indeed some of these variants are present in the corresponding populations.

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“…Since the first report, five additional patients have been described, moreover, adding further clinical features, e.g. pituitary stalk interruption syndrome (Alfadhel et al, 2021; David et al, 2020). In 2021, the condition was named BRENS syndrome (MIM #619534) after its major clinical affections sites: Biliary, Renal, Neurological, and Skeletal (Alfadhel et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip‐palate cleft: A case report and expansion of the phenotype

Papingi,

Bierhals,

Volk

et al. 2023

American J of Med Genetics Pt A

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Biallelic pathogenic variants in the TTC26 gene are known to cause BRENS (biliary, renal, neurological, skeletal) syndrome, an ultra‐rare autosomal recessive condition with only few patients published to date. BRENS syndrome is characterized by hexadactyly, severe neonatal cholestasis, and involvement of the brain, heart, and kidney, however the full phenotypic and genotypic spectrum is unknown. Here, we report on a previously undescribed homozygous intronic TTC26 variant (c.1006‐5 T > C) in a patient showing some of the known TTC26‐associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy, and congenital heart defect. Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip‐palate. The variant is considered to affect correct splicing by the loss of the canonical acceptor splice site and activation of a cryptic acceptor splice site. Hereby, our patient represents one additional patient with BRENS syndrome carrying a previously unreported TTC26 variant. Furthermore, we confirm the involvement of the pituitary gland to be a common clinical feature of the syndrome and broaden the clinical spectrum of TTC26 ciliopathy to include facial clefts and a probable hearing involvement.

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Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy

Cited by 10 publications

References 23 publications

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

Forty‐seven pathogenic variants causing autosomal recessive disorders are shared by Israeli and Saudi Arabian Arabs

A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip‐palate cleft: A case report and expansion of the phenotype

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