Analysis of genetic and clinical characteristics of a Chinese Kallmann syndrome cohort with ANOS1 mutations

Nie, Min; Xu, Hongli; Chen, Rongrong; Mao, Jiangfeng; Wang, Xi; Xiong, Shuyu; Zheng, Junjie; Cui, Mingxuan; Ma, Wanlu; Huang, Qibing; Zhang, Hongbing; Wu, Xueyan

doi:10.1530/eje-17-0335

Cited by 16 publications

(13 citation statements)

References 33 publications

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“…These findings strengthen the importance of these genes in the pathogenesis of CHH. The prevalence of mutations in the classical CHH genes in our cohort is in agreement to the described in the literature, although the frequency of mutations in each specific gene is somehow variable in different publications, possibly due to baseline differences in the selection of populations studied, ethnicity, frequency of familial cases and consanguineous families (5,10,12,32,34,35,37,38,39,40,41).…”

Section: Discussionsupporting

confidence: 89%

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

Amato

Montenegro

Lerário

et al. 2019

European Journal of Endocrinology

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Context Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. Objective Genetic characterization of a large cohort of Brazilian CHH patients. Design and patients A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. Results Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. Conclusions This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.

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Section: Discussionsupporting

confidence: 89%

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

Amato

Montenegro

Lerário

et al. 2019

European Journal of Endocrinology

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“…In familial forms, heterozygous women are always asymptomatic carriers (2,12,(69)(70)(71)(72). However, one series identified 10 women harboring variants.…”

Section: Kal1/anos1mentioning

confidence: 99%

“…Other signs associated with this genetic form, such as mirror movements (also called bimanual synkinesis) and renal agenesis, are frequent, but they do not always cosegregate with the mutation identified in a given family (69,70,(71)(72)(73)(74)(75)(76), for reasons that are still not clear. Other, rarer associated signs such as deafness (35)(36)(37)(38)(69)(70)(71)(72)(73)(74)(75)(76) and vas deferens agenesis, have been described in men with KAL1/ANOS1 mutations (69-74) but their inconsistent presence remains unexplained.…”

Section: Kal1/anos1mentioning

confidence: 99%

“…Other, rarer associated signs such as deafness (35)(36)(37)(38)(69)(70)(71)(72)(73)(74)(75)(76) and vas deferens agenesis, have been described in men with KAL1/ANOS1 mutations (69-74) but their inconsistent presence remains unexplained. Some patients with X-linked KS have large deletions in chromosome region Xp22.3, removing several adjacent genes.…”

Section: Kal1/anos1mentioning

confidence: 99%

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GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Maione

Dwyer

Francou

et al. 2018

European Journal of Endocrinology

132

166

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Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women.However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation.These are genetic diseases that can be transmitted to patients' offspring. Importantly patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex, oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing, and is increasingly being used in medical practice. Thus it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission but also its role in incomplete penetrance and variable expresivity in a perspective of genetic counseling.

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“…Other clinical signs, such as cleft lip, cleft palate, missing teeth, color blindness, optic atrophy, sensorineural hearing loss, functional hypothalamic amenorrhea, unilateral renal aplasia, and genital anomalies occur with less frequency and can be associated with genetic heterogeneity of the condition. [27][28][29][30][31] Hypogonadotropic hypogonadism was not observed in our patient at the time of the last genetic clinical evaluation (10 years old). She had, however, cleft palate and unilateral renal agenesis, both symptoms already associated with the haploinsufficiency of KAL1 gene.…”

Section: Discussionmentioning

confidence: 99%

Microphthalmia, Linear Skin Defects, Callosal Agenesis, and Cleft Palate in a Patient with Deletion at Xp22.3p22.2

et al. 2020

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The authors describe the clinical findings observed in a Brazilian girl that are suggestive of microphthalmia and linear skin defects (MLS) also known as MIDAS syndrome (OMIM #309801). She also presented with short stature, agenesis of corpus callosum, cleft palate, enamel defects, and genitourinary anomalies, which are rarely reported within the clinical spectrum of MLS. The 11,5 Mb deletion in Xp22.3p22.2 observed in the patient includes the entire HCCS gene (responsible for the MLS phenotype) and also encompasses several other genes involved with behavioral phenotypes, craniofacial and central nervous system development such as MID1, NLGN4X, AMELX, ARHGAP6, and TBL1X. The whole clinical features of our proband possibly represents an unusual MLS syndromic phenotype caused by an Xp22.3p22.2 continuous gene deletion.

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Analysis of genetic and clinical characteristics of a Chinese Kallmann syndrome cohort with ANOS1 mutations

Cited by 16 publications

References 33 publications

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Microphthalmia, Linear Skin Defects, Callosal Agenesis, and Cleft Palate in a Patient with Deletion at Xp22.3p22.2

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