Whole-Exome Sequencing Identifies Homozygous GPR161 Mutation in a Family with Pituitary Stalk Interruption Syndrome

Karaca, Ender; Büyükkaya, Ramazan; Pehlivan, Davut; Charng, Wu‐Lin; Yaykaşlı, Kürşat Oğuz; Bayram, Yavuz; Gambin, Tomasz; Withers, Marjorie; Atik, Mehmed M.; Arslanoğlu, İlknur; Bolu, Semih; Erdin, Serkan; Büyükkaya, Ayla; Yaykaşlı, Emine; Jhangiani, Shalini N.; Muzny, Donna M.; Gibbs, Richard A.; Lupski, James R.

doi:10.1210/jc.2014-1984

Cited by 69 publications

(54 citation statements)

References 32 publications

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“…Karaca et al () reported a homozygous missense variant, p. Leu19Gln, in the GPR161 gene as the potential novel cause of pituitary stalk interruption syndrome. In addition, this variant is recognized as likely pathogenic in the ClinVar database.…”

Section: Resultsmentioning

confidence: 99%

Iranome: A catalog of genomic variations in the Iranian population

et al. 2019

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Considering the application of human genome variation databases in precision medicine, population‐specific genome projects are continuously being developed. However, the Middle Eastern population is underrepresented in current databases. Accordingly, we established Iranome database (http://www.iranome.com) by performing whole exome sequencing on 800 individuals from eight major Iranian ethnic groups representing the second largest population of Middle East. We identified 1,575,702 variants of which 308,311 were novel (19.6%). Also, by presenting higher frequency for 37,384 novel or known rare variants, Iranome database can improve the power of molecular diagnosis. Moreover, attainable clinical information makes this database a good resource for classifying pathogenicity of rare variants. Principal components analysis indicated that, apart from Iranian‐Baluchs, Iranian‐Turkmen, and Iranian‐Persian Gulf Islanders, who form their own clusters, rest of the population were genetically linked, forming a super‐population. Furthermore, only 0.6% of novel variants showed counterparts in “Greater Middle East Variome Project”, emphasizing the value of Iranome at national level by releasing a comprehensive catalog of Iranian genomic variations and also filling another gap in the catalog of human genome variations at international level. We introduce Iranome as a resource which may also be applicable in other countries located in neighboring regions historically called Greater Iran (Persia).

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Section: Resultsmentioning

confidence: 99%

Iranome: A catalog of genomic variations in the Iranian population

et al. 2019

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“…Among these mutated genes, transcriptional factor HESX1 ‐mediated repression of Wnt/β‐catenin targets is required for the normal development of anterior forebrain 24; Wnt/β‐catenin signalling promotes midbrain dopaminergic progenitor specification, proliferation and neurogenesis by up‐regulating OTX2 in progenitors 25; Notch signalling has been linked to PROP1 expression 26; GPR161 and CDON , the latest mutations found in patients with PSIS by WES recently, are regulators of Shh pathway 27, 28. Collectively, these pathways seem to be critical to pituitary development.…”

Section: Discussionmentioning

confidence: 99%

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

Guo

Wang

et al. 2017

J Cellular Molecular Medi

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Pituitary stalk interruption syndrome (PSIS) is a rare type of hypopituitarism manifesting various degrees of pituitary hormone deficiency. Although mutations have been identified in some familial cases, the underpinning mechanisms of sporadic patients with PSIS who are in a vast majority remain elusive, necessitating a comprehensive study using systemic approaches. We postulate that other genetic mechanisms may be responsible for the sporadic PSIS. To test this hypothesis, we conducted a study in 24 patients with PSIS of Han Chinese with no family history using whole‐exome sequencing (WES) and bioinformatic analysis. We identified a group of heterozygous mutations in 92% (22 of 24) of the patients, and these genes are mostly associated with Notch, Shh, Wnt signalling pathways. Importantly, 83% (20 of 24) of the patients had more than one mutation in those pathways suggesting synergy of compound mutations underpin the pathogenesis of sporadic PSIS.

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“…Distinct facial features of PSIS were reported by Karaca et al . in two affected siblings from one consanguineous family with PSIS: hypotelorism, sparse hair, broad nasal root and thick ala nasi. Another study indicated facial dysmorphic features, including a broad forehead with frontal bossing, anteverted helix, a high nasal bridge with a bulbous nasal tip and a short chin, and deep philtrum with a thin upper lip and sparse fine hair .…”

Section: Clinical Findingsmentioning

confidence: 97%

“…The high frequency of perinatal events is suggestive of an aetiological relationship between perinatal damage and PSIS. However, the existence of familial cases and the presence of accompanying genetic abnormalities, especially midline defects, point to genetic alterations as the underlying pathogenetic mechanism, at least in some patients .…”

Section: Introductionmentioning

confidence: 99%

Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis

Wang

Guo

Han

et al. 2017

J Neuroendocrinology

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Pituitary stalk interruption syndrome (PSIS) is a rare congenital defect manifesting with varying degrees of pituitary hormone deficiency. The signs and symptoms of PSIS during the neonatal period and infancy are often overlooked and therefore diagnosis is delayed. The typical manifestations of PSIS can be detected by magnetic resonance imaging. Several genes in the Wnt, Notch and Shh signalling pathways related to hypothalamic-pituitary development, such as PIT1, PROP1, LHX3/LHX4, PROKR2, OTX2, TGIF and HESX1, have been found to be associated with PSIS. Nevertheless, the aetiology in the majority of cases still remains unknown. In the present review, we provide an overview of clinical features of PSIS and summarise our current understanding of the underlying pathogenic mechanisms for this rare syndrome. Furthermore, we propose future research directions that may help our understanding of the aetiology of PSIS.

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Whole-Exome Sequencing Identifies Homozygous GPR161 Mutation in a Family with Pituitary Stalk Interruption Syndrome

Abstract: Mutations of GPR161 may be implicated as a potential novel cause of PSIS.

Cited by 69 publications

References 32 publications

Iranome: A catalog of genomic variations in the Iranian population

Iranome: A catalog of genomic variations in the Iranian population

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis

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