Accurate Detection of Intragenic Deletions of KAL1 Gene Using the Multiplex Ligation-Dependent Probe Amplification in Patients with Kallmann Syndrome

Kallmann syndrome (KS)/Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by hypogonadotropic hypogonadism and anosmia or hyposmia due to the abnormal migration of olfactory and gonadotropin releasing hormone producing neurons. Multiple genes have been implicated in KS/IHH. Sequential testing of these genes utilising Sanger sequencing is time consuming and not cost effective. The introduction of parallel multigene panel sequencing of small gene panels for the identification of causative gene variants has been shown to be a robust tool in the clinical setting. Utilizing multiplex PCR for the four gene KS/IHH panel followed by NGS, we describe herewith two cases of hypogonadotropic hypogonadism with a Prokineticin receptor 2 (PROKR2) gene and KAL1 gene mutation. The subject with a PROKR2 mutation had a normal perception of smell and normal olfactory bulbs on imaging. The subject with a KAL1 gene mutation had anosmia and a hypoplastic olfactory bulb.

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Combined use of multiplex ligation-dependent probe amplification and automatic sequencing for identification of KAL1 defects in patients with Kallmann syndrome

Fertility and Sterility ◽

10.1016/j.fertnstert.2013.04.045 ◽

2013 ◽

Vol 100 (3) ◽

pp. 854-859 ◽

Cited By ~ 5

Author(s):

Luciana Ribeiro Montenegro ◽

Leticia F.G. Silveira ◽

Cintia Tusset ◽

Margaret de Castro ◽

Beatriz R. Versiani ◽

...

Keyword(s):

Kallmann Syndrome ◽

Combined Use ◽

Dependent Probe

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A Novel Mutation of the KAL1 Gene in Kallmann Syndrome.

Endocrine Journal ◽

10.1507/endocrj.46.651 ◽

1999 ◽

Vol 46 (5) ◽

pp. 651-658 ◽

Cited By ~ 2

Author(s):

YUKIKO IZUMI ◽

KE-ITA TATSUMI ◽

SHINGO OKAMOTO ◽

AKIKO HOSOKAWA ◽

SATOSHI UENO ◽

...

Keyword(s):

Novel Mutation ◽

Kallmann Syndrome ◽

Kal1 Gene

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A fertile male patient with Kallmann syndrome and two missense mutations in the KAL1 gene

Fertility and Sterility ◽

10.1016/j.fertnstert.2010.11.045 ◽

2011 ◽

Vol 95 (5) ◽

pp. 1789.e3-1789.e6 ◽

Cited By ~ 2

Author(s):

Shilin Zhang ◽

Tao Wang ◽

Jun Yang ◽

Zhuo Liu ◽

Shaogang Wang ◽

...

Keyword(s):

Male Patient ◽

Kallmann Syndrome ◽

Missense Mutations ◽

Kal1 Gene ◽

Fertile Male

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The importance of biochemical and genetic findings in the diagnosis of atypical Norrie disease

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2017-0226 ◽

2018 ◽

Vol 56 (2) ◽

pp. 229-235 ◽

Cited By ~ 2

Author(s):

Ana Rodríguez-Muñoz ◽

Gema García-García ◽

Francisco Menor ◽

José M. Millán ◽

Miguel Tomás-Vila ◽

...

Keyword(s):

High Performance ◽

Cerebellar Atrophy ◽

Chromosomal Microarray ◽

Genetic Studies ◽

Norrie Disease ◽

Acid Protein ◽

Intragenic Deletions ◽

Atypical Phenotype ◽

Amino Acid Protein ◽

Dependent Probe

Abstract Background: Norrie disease (ND) is a rare X-linked disorder characterized by bilateral congenital blindness. ND is caused by a mutation in the Norrie disease pseudoglioma (NDP) gene, which encodes a 133-amino acid protein called norrin. Intragenic deletions including NDP and adjacent genes have been identified in ND patients with a more severe neurologic phenotype. We report the biochemical, molecular, clinical and radiological features of two unrelated affected males with a deletion including NDP and MAO genes. Methods: Biochemical and genetic analyses were performed to understand the atypical phenotype and radiological findings. Biogenic amines in cerebrospinal fluid (CSF) were measured by high-performance liquid chromatography. The coding exons of NDP gene were amplified by polymerase chain reaction. Multiplex ligation-dependent probe amplification and chromosomal microarray were carried out on both affected males. Computed tomography and magnetic resonance imaging were performed on the two patients. Results: In one patient, the serotonin and catecholamine metabolite levels in CSF were virtually undetectable. In both patients, genetic studies revealed microdeletions in the Xp11.3 region, involving the NDP, MAOA and MAOB genes. Radiological examination demonstrated brain and cerebellar atrophy. Conclusions: We suggest that alterations caused by MAO deficit may remain during the first years of life. Clinical phenotype, biochemical findings and neuroimaging can guide the genetic study in patients with atypical ND and help us to a better understanding of this disease.

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A novel mutation of the KAL1 gene in monozygotic twins with Kallmann syndrome

Acta Endocrinologica ◽

10.1530/eje.0.1430783 ◽

2000 ◽

pp. 783-787 ◽

Cited By ~ 15

Author(s):

T Matsuo ◽

S Okamoto ◽

Y Izumi ◽

A Hosokawa ◽

T Takegawa ◽

...

Keyword(s):

Novel Mutation ◽

Direct Sequencing ◽

Hypogonadotropic Hypogonadism ◽

Monozygotic Twins ◽

Kallmann Syndrome ◽

Gene Design ◽

Kal1 Gene ◽

Sequencing Method ◽

Exon 9 ◽

Lh Rh

OBJECTIVE: Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. The KAL1 gene is responsible for the X-linked form of Kallmann syndrome. In this study we describe monozygotic twins with Kallmann syndrome due to the same mutation in the KAL1 gene. DESIGN: We studied male monozygotic twins with Kallmann syndrome. METHODS: We analyzed the KAL1 gene using the PCR-direct sequencing method. The twins' mother was examined for the identified mutation. RESULTS: We identified a 14 bp deletion from codon 419 in exon 9 (Pro419del14) in both KAL1 genes of the twins. This was a novel mutation in the KAL1 gene and was responsible for Kallmann syndrome. As Pro419del14 was not detected in the mother of the twins, Pro419del14 was a germline mutation originating from them. These monozygotic twins showed different LH and FSH responses to LH-RH stimulation and different phenotypes such as complications, physiques and psychiatric characters. CONCLUSIONS: We report an identical KAL1 gene mutation in the monozygotic twins with Kallmann syndrome. As these monozygotic twins showed different phenotypes in some respects, we suggest that factors other than mutations in the KAL1gene affect the symptomatic features of Kallmann syndrome.

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