Isodicentric Y chromosome with multiple breakpoints in the pseudoautosomal region 1.

INTRODUCTION: Isodicentric Y chromosomes are relatively common structural variants of the human genome. The underlying mechanism of isodicentric Y chromosomes with short arm breakpoints [idic(Yq)] remains to be clarified. CASE PRESENTATION: We encountered a Japanese man with azoospermia and mild short stature. G-banding and array-based comparative genomic hybridization indicated that his karyotype was 45,X/46,X,idic(Y)(qter→p11.32::p11.32→qter) with a ~1.8 Mb terminal deletion. Whole genome sequencing suggested that the Y chromosome had four breakpoints in a ~7 kb region of the pseudoautosomal region 1 (PAR1). CONCLUSION: This case was assumed to have an idic(Yq) resulting from multiple DNA double-strand breaks in PAR1. This rearrangement may have been facilitated by the PAR1-specific chromatin architecture. The clinical features of the patient can be ascribed to SHOX haploinsufficiency and the presence of a 45,X cell line, although copy-number gains of some Yq genes and the size reduction of PAR1 may also contribute to his spermatogenic failure.

Genetic variants of G-protein coupled receptors associated with pubertal disorders.

Background: The human hypothalamic-pituitary-gonadal (HPG) axis is the regulatory center for pubertal development. This axis involves six G-protein coupled receptors (GPCRs) encoded by KISS1R, TACR3, PROKR2, GNRHR, LHCGR, and FSHR. Methods: Previous studies have identified several rare variants of the six GPCR genes in patients with pubertal disorders. In vitro assays and animal studies have provided information on the function of wild-type and variant GPCRs. Main Findings: Of the six GPCRs, those encoded by KISS1R and TACR3 are likely to reside at the top of the HPG axis. Several loss-of-function variants in the six genes were shown to cause late/absent puberty. In particular, variants in KISS1R, TACR3, PROKR2, and GNRHR lead to hypogonadotropic hypogonadism in autosomal dominant, recessive, and oligogenic manners. Furthermore, a few gain-of-function variants of KISS1R, PROKR2, and LHCGR have been implicated in precocious puberty. The human HPG axis may contain additional GPCRs. Conclusion: The six GPCRs in the HPG axis govern pubertal development through fine-tuning of hormone secretion. Rare sequence variants in these genes jointly account for a certain percentage of genetic causes of pubertal disorders. Still, much remains to be clarified about the molecular network involving the six GPCRs.

TAFRO syndrome complicated by porto-sinusoidal vascular liver disease with portal hypertension: a case report.

Porto-sinusoidal vascular liver disease (PSVD) is a disorder that can cause portal hypertension without liver cirrhosis. TAFRO syndrome is a systemic inflammatory disorder with a background of immunological abnormalities. We report a case of TAFRO syndrome complicated by PSVD with portal hypertension. A 39-year-old man developed refractory ascites and esophageal varices. Lymph node histology revealed multicentric Castleman disease-like features. Intravenous methylprednisolone and tocilizumab therapy improved ascites and renal dysfunction, but the patient developed severe infections. The diagnosis of TAFRO syndrome in patients complicated by PSVD with portal hypertension encourages the consideration of appropriate treatment for these patients.

Methylation status of genes escaping from X-chromosome inactivation in patients with X-chromosome rearrangements.

BACKGROUND: X-chromosome inactivation (XCI) is a mechanism in which one of two X chromosomes in females is randomly inactivated in order to compensate for imbalance of gene dosage between sexes. However, about 15% of genes on the inactivated X chromosome (Xi) escape from XCI. The methylation level of the promoter region of the escape gene is lower than that of the inactivated genes. Dxz4 and/or Firre have critical roles for forming the three-dimensional (3D) structure of Xi. In mice, disrupting the 3D structure of Xi by deleting both Dxz4 and Firre genes led to changing of the escape genes list. To estimate the impact for escape genes by X-chromosome rearrangements, including DXZ4 and FIRRE, we examined the methylation status of escape gene promoters in patients with various X-chromosome rearrangements. RESULTS: To detect the breakpoints, we first performed array-based comparative genomic hybridization and whole-genome sequencing in four patients with X-chromosome rearrangements. Subsequently, we conducted array-based methylation analysis and reduced representation bisulfite sequencing in the four patients with X-chromosome rearrangements and controls. Of genes reported as escape genes by gene expression analysis using human hybrid cells in a previous study, 32 genes showed hypomethylation of the promoter region in both male controls and female controls. Three patients with X-chromosome rearrangements had no escape genes with abnormal methylation of the promoter region. One of four patients with the most complicated rearrangements exhibited abnormal methylation in three escape genes. Furthermore, in the patient with the deletion of the FIRRE gene and the duplication of DXZ4, most escape genes remained hypomethylated. CONCLUSION: X-chromosome rearrangements are unlikely to affect the methylation status of the promoter regions of escape genes, except for a specific case with highly complex rearrangements, including the deletion of the FIRRE gene and the duplication of DXZ4.

SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome.

INTRODUCTION: Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although SOX10, a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH) has previously been implicated in KS, the clinical significance of SOX10 variants as the cause of KS remains uncertain. PATIENTS AND METHODS: A total of 117 patients with KS underwent mutation screening of SOX10 and 14 other causative genes for KS/HH. Rare SOX10 variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with SOX10 variants. RESULTS: Sequence analysis identified 2 heterozygous variants of SOX10 (c.1225G > T, p.Gly409* and c.475C > T, p.Arg159Trp) in patients 1-3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the MITF promoter and exerted no dominant-negative effects. Patients 1-3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the 5 variant-positive individuals exhibited hypopigmentation, while 1 and 2 individuals exhibited complete and partial hearing loss, respectively. CONCLUSION: These results provide evidence that SOX10 haploinsufficiency accounts for a small percentage of KS cases. SOX10 haploinsufficiency is likely to be associated with a broad phenotypic spectrum, which includes KS without other clinical features of WS/PCWH.

Structural and numerical Y chromosomal variations in elderly men identified through multiplex ligation-dependent probe amplification.

Human Y chromosomes frequently acquire structural and numerical alterations. Known alterations include germline copy-number variations (CNVs) in the azoospermia factor (AZF) region and somatic mosaic loss of the Y chromosome (mLOY). Here, we explored Y chromosomal variations in 160 Japanese men aged 75-90 years. Multiplex ligation-dependent probe amplification (MLPA) identified ten types of AZF-linked CNVs in 77 men and mLOY of various degrees in 37. Seventeen men carried both a CNV and mLOY. MLOY levels estimated by MLPA were closely correlated with those determined by droplet digital PCR. No association was found between AZF-linked CNVs and the frequency or levels of mLOY. These results emphasize the high frequency and large inter-individual variability of AZF-linked CNVs and mLOY, and demonstrate the usefulness of MLPA in the detection of these variations. More importantly, this study provides the first evidence that AZF-linked CNVs do not increase the risk of aging-related mLOY.

Labor dystocia and risk of histological chorioamnionitis and funisitis: a study from a single tertiary referral center.

BACKGROUND: Intrauterine inflammation affects short- and long-term neonatal outcomes. Histological chorioamnionitis and funisitis are acute inflammatory responses in the fetal membranes and umbilical cord, respectively. Although labor dystocia includes a potential risk of intrauterine inflammation, the risk of histological chorioamnionitis and funisitis of labor dystocia has not been evaluated yet. This study aimed to examine the association between labor dystocia and risk of histological chorioamnionitis and funisitis. METHODS: In this retrospective cohort study, the cases who underwent histopathological examinations of the placenta and umbilical cord at Fukushima Medical University Hospital, Japan, between 2015 and 2020, were included. From the dataset, the pathological findings of the patients with labor dystocia and spontaneous preterm birth were reviewed. Based on the location of leukocytes, the inflammation in the placenta (histological chorioamnionitis) and umbilical cord (funisitis) was staged as 0-3. Multiple logistic regression analysis was performed to evaluate the risk of histological chorioamnionitis, histological chorioamnionitis stage ≥2, funisitis, and funisitis stage ≥2. RESULT: Of 317 women who met the study criteria, 83 and 144 women had labor dystocia and spontaneous preterm birth, respectively, and 90 women were included as controls. Labor dystocia was a risk factor for histological chorioamnionitis (adjusted odds ratio, 6.3; 95% confidential interval, 1.9-20.5), histological chorioamnionitis stage ≥2 (adjusted odds ratio, 6.0; 95% confidence interval, 1.7-21.8), funisitis (adjusted odds ratio, 15.4; 95% confidence interval, 2.3-101.3), and funisitis stage ≥2 (adjusted odds ratio, 18.5; 95% confidence interval, 2.5-134.0). Spontaneous preterm birth was also a risk factor for histological chorioamnionitis (adjusted odds ratio, 3.7; 95% confidence interval, 1.7-7.8), histological chorioamnionitis stage ≥2 (adjusted odds ratio, 3.0; 95% confidence interval, 1.2-7.9), and funisitis (adjusted odds ratio, 6.6; 95% confidence interval, 1.4-30.6). However, the adjusted odds ratio was smaller in spontaneous preterm births than in labor dystocia. CONCLUSION: Labor dystocia is a risk factor for severe histological chorioamnionitis and funisitis. Further studies are required to evaluate the effects of histological chorioamnionitis and funisitis on long-term neonatal outcomes.

NDNF variants are rare in patients with congenital hypogonadotropic hypogonadism.

Although NDNF was recently reported as a novel causative gene for congenital hypogonadotropic hypogonadism (CHH), this conclusion has yet to be validated. In this study, we sequenced NDNF in 61 Japanese CHH patients. No variants, except for nine synonymous substitutions that appear to have no effect on splice-site recognition, were identified in NDNF coding exons or flanking intronic sequences. These results indicate the rarity of NDNF variants in CHH patients and highlight the genetic heterogeneity of CHH.

Efficacies of first and second tumor necrosis factor inhibitors in refractory ulcerative colitis patients in real-world practice.

BACKGROUND: Switching tumor necrosis factor-α inhibitors is an important treatment option for refractory ulcerative colitis (UC) patients who fail the first anti-tumor necrosis factor-α therapy, although many questions about this option remain unanswered. METHODS: The efficacy of the second anti-tumor necrosis factor-α therapy in refractory UC patients who failed the first anti-tumor necrosis factor-α therapy was examined using the Mayo score as a measure of disease activity at week 8. The efficacy of the first anti-tumor necrosis factor-α therapy before treatment and at weeks 8 and 52 was also evaluated in real-world practice. RESULTS: There were no significant differences in remission induction and maintenance between infliximab and adalimumab as the first anti-tumor necrosis factor-α therapy in UC patients. Of 123 UC patients, 21 (17.1%) switched tumor necrosis factor-α inhibitors. Eight (38.1%), 4 (19.0%), 7 (33.3%), and 2 (9.5%) patients switched from infliximab to adalimumab, infliximab to golimumab, adalimumab to infliximab, and adalimumab to golimumab, respectively. Three (100%) with intolerance to the first anti-tumor necrosis factor-α therapy, 5 (41.7%) with loss of response to the first anti-tumor necrosis factor-α therapy, and 1 (20.0%) with no improvement with the first anti-tumor necrosis factor-α therapy had clinical remission at week 8. CONCLUSIONS: Switching tumor necrosis factor-α inhibitors is more effective for refractory UC patients who are intolerant and lose response to the first anti-tumor necrosis factor-α therapy rather than for those showing no improvement with the first anti-tumor necrosis factor-α therapy. Patients with primary failure of anti-tumor necrosis factor-α therapy should be switched to another class of drug.

IgG4-Related Disease Complicated by Brain Parenchymal Lesions Successfully Treated with Corticosteroid Therapy: A Case Report.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is distinguished by the infiltration of IgG4-positive plasma cells in a variety of tissues and organs including the pancreas, salivary glands, retroperitoneal lesions, kidney, and lymph nodes with elevated serum IgG4 levels. Even so, central nervous system (CNS) lesions such as brain parenchymal lesions associated with IgG4-RD are scarce. So far, only six cases of IgG4-RD in relation with brain parenchymal lesions have been described, with its characteristics still being not clear. Here we have detailed a case of IgG4-RD with brain parenchymal lesions and reviewed previously-reported cases of IgG4-RD with brain parenchymal lesions. A 62-year-old Japanese male suffering from lung silicosis was admitted to our hospital for abdominal discomfort and altered consciousness. He has shown no major neurologic abnormalities except for drowsiness, urinary retention, and fecal incontinence. Brain magnetic resonance imaging has shown scattered hyperintense signals in the brain parenchyma. The serum IgG4 levels were elevated and systemic lymph nodes were enlarged. Biopsy from inguinal lymph nodes has shown massive infiltration of IgG4-positive plasma cells: the ratio of IgG4-positive/IgG-positive plasma cells was nearly 100%. Based on clinical courses, images, laboratory data, and pathological findings, a diagnosis of IgG4-RD that was complicated by brain parenchymal lesions and sacral nerve disturbance was confirmed. The patient was then given methylprednisolone pulse therapy (1g for 3 days) succeeding oral prednisolone (1 mg per body weight). The clinical and radiological improvements together with steroid therapy proposed IgG4-RD to be the cause of the lesions.

Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency.

Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum.

Copy-number analysis of Y-linked loci in young men with non-obstructive azoospermia: Implications for the rarity of early onset mosaic loss of chromosome Y.

PURPOSE: Mosaic loss of chromosome Y (mLOY) is a common feature in elderly men. If mLOY can also occur in young men, it may lead to spermatogenic failure due to loss of spermatogenic genes. Indeed, previous studies detected the 45,X/46,XY karyotype in a few young men with spermatogenic failure. The present study aimed to clarify the frequency of cryptic mLOY in reproductive-aged men with spermatogenic failure. METHODS: We studied 198 men at ages 24-55 years who presented with etiology-unknown non-obstructive azoospermia. Prior this study, these patients underwent G-banding analysis for 20 leukocytes and were found to have 46,XY karyotype. We analyzed copy numbers of chromosome Y in blood cells by using semi-quantitative multiplex PCR for AMELY/AMELX, array-based comparative genomic hybridization (CGH) for the AMELY locus, and droplet digital PCR for SRY, USP9Y, and UTY. RESULTS: Multiplex PCR showed borderline low AMELY/AMELX ratios in three patients. However, for the three patients, CGH excluded deletion of the AMELY locus, and droplet digital PCR suggested preserved copy numbers of all tested loci. CONCLUSION: This study highlights the rarity of leukocyte mLOY in reproductive-aged men with spermatogenic failure. In addition, our data imply that standard karyotyping is sufficient to screen early onset mLOY.

Intraclass correlations of seizure duration by wavelet transform, sample entropy, and visual determination in electroconvulsive therapy.

Although electroconvulsive therapy seizure duration has been shown to have limited relevance to efficacy, seizure duration remains important for clinically valid stimulus efficiency. There has been no report on seizure duration using sample entropy with Thymatron (Somatics, Inc), which is widely used in Japan. Furthermore, wavelet transform analysis is also suitable for a seizure because of the wide range of dominant frequencies. Therefore, in this study with Thymatron, the intraclass correlations of seizure duration determined by sample entropy, wavelet transform, and visual determination were investigated to determine whether these methods were applicable for clinical use. Wavelet transform, sample entropy, and the human rater had high intraclass correlations for seizure duration. The present results indicate that wavelet transform and sample entropy can be useful in the clinical electroconvulsive therapy setting, and they may also be suitable for clinical research into the mechanisms of the generalized tonic-clonic seizures related to the efficacy of electroconvulsive therapy.

Random X chromosome inactivation in patients with Klinefelter syndrome.

BACKGROUND: X chromosome inactivation (XCI) is an indispensable process in the development of human female embryos. Reportedly, XCI occurs when a blastocyst contains 10-12 embryonic progenitor cells. To date, it remains unclear whether XCI ratios are normally preserved in Klinefelter syndrome (KS) patients with 47,XXY karyotype. METHODS: We examined XCI ratios in 18 KS patients through DNA methylation analysis for the polymorphic trinucleotide locus in the AR gene. The results of the KS patients were compared to previous data from healthy young women. RESULTS: XCI ratios in KS patients followed a normal distribution. Skewed XCI was observed in two patients, one of whom exhibited extremely skewed XCI. The frequencies of skewed and extremely skewed XCI in the KS cohort were comparable to those in healthy women. CONCLUSION: This study confirmed the rarity of skewed XCI in KS patients. These results indicate that the presence of a supernumerary X chromosome during the cleavage and early blastocyst stages does not affect the developmental tempo of embryos. Our data deserve further validation.

WDR11 is another causative gene for coloboma, cardiac anomaly and growth retardation in 10q26 deletion syndrome.

10q26 deletion syndrome is caused by a rare chromosomal abnormality, and patients with this syndrome present with an extensive and heterogeneous phenotypic spectrum. Several genes, such as EMX2 and FGFR2, were identified as the cause genital anomalies and facial dysmorphism in 10q26 deletion syndrome. However, the critical region for 10q26 deletion syndrome is not determined and the precise relationships between the causative genes and the phenotypes are still controversial. WD repeat domain 11 (WDR11), located at 10q25-26, was recently identified as a causative gene in hypogonadotropic hypogonadism, but other clinical phenotypes caused by WDR11 variants have not been identified. In this study, we have identified a WDR11 missense mutation, NM_018117.11: c.2108G > A; p.(Arg703Gln); ClinVar accession SCV000852064, in a two-year-old boy with severe growth retardation, ventricular septal defect, and coloboma symptoms. The case suggests that WDR11 is partially responsible for the clinical features of 10q26 deletion syndrome and provides novel insights into the pathophysiology of this syndrome.

DNA Methylation Status of SHOX-Flanking CpG Islands in Healthy Individuals and Short Stature Patients with Pseudoautosomal Copy Number Variations.

SHOX resides in the short arm pseudoautosomal region (PAR1) of the sex chromosomes and escapes X inactivation. SHOX haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). A substantial percentage of cases with SHOX haploinsufficiency arise from pseudoautosomal copy number variations (CNVs) involving putative enhancer regions of SHOX. Our previous study using peripheral blood samples showed that some CpG dinucleotides adjacent to SHOX exon 1 were hypomethylated in a healthy woman and methylated in a woman with gross X chromosomal rearrangements. However, it remains unknown whether submicroscopic pseudoautosomal CNVs cause aberrant DNA methylation of SHOX-flanking CpG islands. In this study, we examined the DNA methylation status of SHOX-flanking CpG islands in 50 healthy individuals and 10 ISS/LWD patients with pseudoautosomal CNVs. In silico analysis detected 3 CpG islands within the 20-kb region from the translation start site of SHOX. Pyrosequencing and bisulfite sequencing of genomic DNA samples revealed that these CpG islands were barely methylated in peripheral blood cells and cultured chondrocytes of healthy individuals, as well as in peripheral blood cells of ISS/LWD patients with pseudoautosomal CNVs. These results, in conjunction with our previous findings, indicate that the DNA methylation status of SHOX-flanking CpG islands can be affected by gross X-chromosomal abnormalities, but not by submicroscopic CNVs in PAR1. Such CNVs likely disturb SHOX expression through DNA methylation-independent mechanisms, which need to be determined in future studies.

(Epi)genetic defects of MKRN3 are rare in Asian patients with central precocious puberty.

We sequenced MKRN3, the major causative gene of central precocious puberty in Western countries, in 24 Japanese or Chinese patients and examined the DNA methylation and copy-number statuses of this gene in 19 patients. We identified no (epi)genetic defects except for one previously reported mutation. These results, together with reports from Korea, indicate that MKRN3 defects are rare in Asian populations. The ethnic differences likely reflect Western country-specific founder mutations and the rarity of de novo mutations.

Gain-of-function mutations in G-protein-coupled receptor genes associated with human endocrine disorders.

The human genome encodes more than 700 G-protein-coupled receptors (GPCRs), many of which are involved in hormone secretion. To date, more than 100 gain-of-function (activating) mutations in at least ten genes for GPCRs, in addition to several loss-of-function mutations, have been implicated in human endocrine disorders. Previously reported gain-of-function GPCR mutations comprise various missense substitutions, frameshift mutations, intragenic inframe deletions and copy-number gains. Such mutations appear in both germline and somatic tumour cells, and lead to various hormonal abnormalities reflecting excessive receptor activity. Phenotypic consequences of these mutations include distinctive endocrine syndromes, as well as relatively common hormonal abnormalities. Such mutations encode hyperfunctioning receptors with increased constitutive activity, broadened ligand specificity, increased ligand sensitivity and/or delayed receptor desensitization. Furthermore, recent studies proposed a paradoxical gain-of-function mechanism caused by inactive GPCR mutants. Molecular diagnosis of GPCR activating mutations serves to improve the clinical management of mutation-positive patients. This review aims to introduce new aspects regarding gain-of-function mutations in GPCR genes associated with endocrine disorders.

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature.

Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.

SOX2 nonsense mutation in a patient clinically diagnosed with non-syndromic hypogonadotropic hypogonadism.

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.