A Novel Mutation in SOX2 Causes Hypogonadotropic Hypogonadism with Mild Ocular Malformation

Takagi, Masaki; Narumi, Shunji; Asakura, Yumi; Muroya, Koji; Hasegawa, Yukihiro; Adachi, Masanori; Hasegawa, Tomonobu

doi:10.1159/000355279

Cited by 16 publications

(18 citation statements)

References 17 publications

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“…After obtaining written informed consent for the molecular study from the patient and his parents, peripheral blood genomic DNA was isolated. We tested 46 genes associated with isolated or combined pituitary hormone deficiency, including IGSF1 , using a MiSeq instrument (Illumina Inc., San Diego, Calif., USA) according to the SureSelect protocol (Agilent Technologies, Santa Clara, Calif., USA), as previously described [6] with minor modifications. The identified IGSF1 mutation was confirmed by conventional PCR-based Sanger sequencing.…”

Section: Case Reportmentioning

confidence: 99%

Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1

et al. 2015

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Background: Recent reports have indicated that loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1, OMIM 300888) cause congenital central hypothyroidism with macroorchidism. Methods: We conducted a next-generation sequencing-based comprehensive mutation screening for pituitary hormone deficiencies to elucidate molecular mechanisms other than anatomical abnormalities of the pituitary that might be responsible for multiple anterior hormone deficiency in a male patient who originally visited our institute complaining of short stature. He was born large for gestational age (4,370 g, +3.0 SD) after an obstructed labour. Endocrinological evaluation revealed growth hormone and thyroid-stimulating hormone deficiency. Magnetic resonance imaging showed a discontinuity of the pituitary stalk with an ectopic posterior lobe and a hypoplastic anterior lobe, likely explaining multiple anterior pituitary hormone deficiency. Result: We identified a novel hemizygous IGSF1 mutation (c.1137_1138delCA, p.Asn380Glnfs*6) in the patient. In reviewing the literature, we noticed that all reported Japanese male IGSF1 mutation carriers were born larger than mean standards for gestational age (mean birth weight SD score of +2.0, 95% confidence interval 1.0-3.0). Conclusion: This case suggests that more attention should be paid to intrauterine growth and birth history when patients are suspected of having an IGSF1 mutation.

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Section: Case Reportmentioning

confidence: 99%

Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1

et al. 2015

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“…Y110 is a critical amino acid near the DNA-binding HMG region. Mutation attenuates the activation of the downstream target gene HESX1 [30]. While the patient in our study occurred a nonsense mutation at this site, and it's speculated that the mutation would have a greater impact on target gene activation and subsequent gonadotropin levels.…”

Section: Sox2 May Cooperate With Other Pathogenic Genes Associated Wimentioning

confidence: 68%

“…Heterozygous mutations in the SOX2 gene could lead to syndromic HH with A/M/coloboma [4,5,9]. Since 2003, only 6 cases (4.9%) of patients with non-syndromic HH (except for absense of puberty, some patients also show micropenis and/or cryptorchidism) have been reported [8,11,14,30,[38][39], while micropenis and cyptorchidism are the main clues of HH during childhood. The 3 patients in our study are currently young and need further follow-up.…”

Section: Sox2 May Cooperate With Other Pathogenic Genes Associated Wimentioning

confidence: 99%

SOX2 heterozygous mutation causes multiple extra-ocular phenotypes in boys

Wang

Fan

Ren

et al. 2020

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Background The SOX2 gene is widely expressed in the eyes and the central nervous system. Heterozygous mutations could cause eye malformations and hypopituitarism, and serve as the causative gene for syndromic and non-syndromic hypogonadotropic hypogonadism (HH). Our study reports three children with chromosome 46, XY, SRY (+), but SOX2 mutations.Methods Three children visited our endocrine clinic because of micropenis and/or cryptorchidism. Clinical data were collected, and one took PANEL sequencing and the others for whole exome sequencing. Then we summarized characteristics of the patients and compared with those mentioned in literature.Results Patient 1 manifested with micropenis, patient 2 with bilateral cryptorchidism and craniofacial deformities, both carrying the same reported SOX2 gene mutation (T232N), and both mutations from mothers with delayed puberty only. Patient 3 showed micropenis, mental retardation and craniofacial deformities, and the child carried a spontaneous truncation mutation (Y110X) of the SOX2 gene. This site has reported that a missense mutation caused adolescent adolescence without major eye signs. All three patients carried another gene mutations that affected hypothalamic-pituitary function: Patient 1, FGFR1: c.238C>T/p.R80C (uncertain) from father; Patient 2, CHD7: c.2656C>T/p.R886W (pathogenic) de novo; Patient 3, SEMA3A: c.1432G> A/p.E478K (uncertain) from mother. None had major ocular malformations, and all showed genitourinary tract malformations. Two patients had craniofacial deformities, and one patient had muscle anomality and intellectual disability. We summarized previous studies with SOX2 gene mutations and it showed: 71.2% of mutations are de novo, all patients reported whose variants inherit from parents, 15.1% parents (including mother 11.0% and father 4.1%) show completely normal phenotypes, 4.1% (3/73) variants inherit from mother with germinal mosaicism. Except for major ocular malformations (91.1%), the most common phenotype is developmental delay/mental retardation (DD/MR), accounting for 40.7%, followed by brain anomely (BA), accounting for 28.5%, male genital abnormalities (GA) for 20.3%, non-syndromic HH accounted for 4.9%, the younger the patients visit the doctor, the more common the retardation are. Conclusion SOX2 mutations could cause a broad phenotype spectrum from completely normal to severe ocular malformations, retardation and most mutations are de novo. Except for major ocular malformations and retardation, GA/HH is another common symptom. GA/HH may be the only symptom, and SOX2 may cooperate with another HH pathogenic genes to cause non-syndromic HH.

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“…factor involved in the development of eyes, pituitary, and central nervous system [1,3,6,13]. To date, heterozygous SOX2 mutations/deletions have been identified in more than 100 individuals [6][7][8][9][10][11][12][14][15][16][17][18][19][20][21]. These abnormalities typically lead to anophthalmia, microphthalmia, or coloboma, in addition to other neurological defects such as HH, brain anomaly, intellectual disability, epilepsy, and hearing loss [6][7][8][9][10][11][15][16][17][18][19][20][21].…”

mentioning

confidence: 99%

“…These abnormalities typically lead to anophthalmia, microphthalmia, or coloboma, in addition to other neurological defects such as HH, brain anomaly, intellectual disability, epilepsy, and hearing loss [6][7][8][9][10][11][15][16][17][18][19][20][21]. Ocular anomalies were documented in almost all known cases with SOX2 haploinsufficiency, while HH was observed in a substantial fraction of the cases [6][7][8][9][10][11][12][14][15][16][17][18][19][20][21].…”

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<i>SOX2</i> nonsense mutation in a patient clinically diagnosed with non-syndromic hypogonadotropic hypogonadism

et al. 2017

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Hypogonadotropic hypogonadism (HH) is a genetically heterogeneous condition that occurs either as an isolated disorder or as a component of congenital malformation syndromes. SOX2 is a causative gene of syndromic HH characterized by anophthalmia, microphthalmia, or coloboma and other neurological defects such as epilepsy. To date, the causal relationship between SOX2 abnormalities and non-syndromic HH remains speculative. Here, we identified a nonsense mutation of SOX2 in a male patient clinically diagnosed with non-syndromic HH. The patient had epilepsy but no additional clinical features. Ophthalmological examination revealed no abnormalities except for decreased thickness of the retinal nerve fiber layer. Audiometry showed mild sensorineural hearing impairment of both ears. Hormonal evaluation suggested isolated gonadotropin deficiency. Next-generation sequencing-based mutation screening of 13 major causative genes for HH identified a p.Lys35 mutation in SOX2 and excluded pathogenic mutations in other tested genes. The p.Lys35 mutation appeared to encode a non-functioning SOX2 protein that lacks 283 of 317 amino acids. The SOX2 mutation was absent in the maternal DNA sample, while a paternal sample was unavailable for sequence analysis. These results expand the clinical consequences of SOX2 haploinsufficiency to include non-syndromic HH. Systematic mutation screening using a next-generation sequencer and detailed evaluation of nonspecific ocular/neurological features may help identify SOX2 mutation-positive individuals among HH patients.

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A Novel Mutation in SOX2 Causes Hypogonadotropic Hypogonadism with Mild Ocular Malformation

Cited by 16 publications

References 17 publications

Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1

Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1

SOX2 heterozygous mutation causes multiple extra-ocular phenotypes in boys

<i>SOX2</i> nonsense mutation in a patient clinically diagnosed with non-syndromic hypogonadotropic hypogonadism

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