Novel interstitial deletion in Xp22.3 in a typical X-linked recessive family with Kallmann syndrome

Abstract

Kallmann syndrome (KS) is a clinically and genetically heterogeneous condition characterised by hypogonadotropic hypogonadism with anosmia or hyposmia. More than nineteen genes causing KS have been reported to date. KAL1, first identified to causing the X-linked form of KS, accounts for 10%-20% of KS patients. In this study, we designed a panel including 17 known genes causing KS for genetic diagnosis and research and report a typical and rare family of which three generations had been affected by KS. A novel CNV in Xp22.3 was identified through targeted next-sequencing technology and high-resolution microarray. The breakpoint (chrX:8536480 and chrX:8730416) was defined, and the size of deletion is about 0.24 Mb. The CNV including KAL1 and FAM9A had a negative effect on the expression of KAL1, resulting in decreased level of KAL1 mRNA in whole blood. In addition, the proband had significant improvement in testicular volumes and secondary sex characters except spermatogenesis after regular treatment, which indicates the CNV may have a negative effect on spermatogenesis. Our study expands the genotypic spectrum of KAL1 mutations associated with KS and provides a practical pipeline for genetic diagnosis or research.

Microcephaly/Trigonocephaly, Intellectual Disability, Autism Spectrum Disorder, and Atypical Dysmorphic Features in a Boy with Xp22.31 Duplication

“…The modalities of presentation in individuals with Xp22.31 duplication might be explained by variable expressivity, decreased penetrance, and skewed X-inactivation [Scharer et al, 2008;Preumont et al, 2010;Niu et al, 2018]. All of these hypotheses need to be further confirmed.…”

“…The Xp22.31 deletion has been reported in association with X-linked ichthyosis, a dermatologic disorder presenting with dry, scaly skin due to a deficiency of the enzyme steroid sulfatase (STS), usually arising from a mutation in the STS gene [Ballabio et al, 1987;Sitek et al, 2018]. Deletions of this region can also involve the KALIG1 gene, which is associated with a disorder manifesting with anosmia and hypogonadotropic hypogonadism called Kallman syndrome [Bick et al, 1992;Niu et al, 2018].…”

Olfactory function and olfactory bulbs in patients with Kallmann syndrome

“…По результатам полногеномного секвенирования с неглубоким покрытием выявлена делеция участка Х-хромосомы, содержащего гены ANOS1, STS, NLGN4X и др. Выпадение гена ANOS1 (он же KAL1) ассоциировано с развитием Х-сцепленного гипогонадотропного гипогонадизма [ 15 ] и аносмии, выпадение гена стероидной сульфатазы STS — с ихтиозом [ 16 ], а гена NLGN4X — c аутизмом [ 17 ], что, вероятно, объясняет нарушения поведения. У пациента 4 была диагностирована меньшая по протяженности делеция Х хромосомы с генами ANOS1, STS, VCX, PNPLA4, VCX2, VCX3B, PUDP, чем объясняется наличие у пациента ихтиоза с гипогонадизмом без нарушений поведения.…”