Whole exome sequencing identified a novel truncation mutation in the NHS gene associated with Nance-Horan syndrome

Ling, Chao; Sui, Ruifang; Yao, Feng; Wu, Zhihong; Zhang, Xue; Zhang, Shuyang

doi:10.1186/s12881-018-0725-3

Cited by 13 publications

(12 citation statements)

References 17 publications

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“…Azoospermia is, however, not a feature of this syndrome. Missense or frameshift pathogenic variants or partial or whole NHS gene deletions are well recognized [19][20][21] , including contiguous deletion of the SCML1 and RA12 genes [Fig. 2].…”

Section: Discussionmentioning

confidence: 99%

A contiguous microdeletion syndrome at Xp23.13 with non-obstructive azoospermia and congenital cataracts

Milunsky

Dong

et al. 2020

J Assist Reprod Genet

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Non-obstructive azoospermia accounts for 10-15% of male infertility, resulting in 60% of all cases of azoospermia and affecting about 1% of the male population. About 30% of these cases are due to Y chromosome microdeletions, chromosome abnormalities, or hormonal disorders. Pathogenic variants in genes on the sex chromosomes have key roles in spermatogenic failure. The co-occurrence of azoospermia and congenital cataracts ranges between 1 in 165,000 and 1 in 500,000. Our 28-year-old patient with normal intelligence and abnormally shaped teeth presented with both disorders. A microarray revealed a microdeletion at Xp23.13 with a whole NHS gene deletion as well as a contiguous deletion of two other genes [SCML1 and RAI2]. This observation represents the first report of non-obstructive azoospermia with congenital cataracts and a contiguous deletion of the SCML1 gene, a transcript of which is exclusively expressed in the testis. SCML1 is the putative culprit gene, which requires functional study or animal experiments. Our analysis of 60 known spermatogenesis failure-related genes by whole-exome sequencing revealed no other candidate. The Nance-Horan syndrome due to pathogenic variants in the NHS gene at Xp23.13 including whole gene deletion does not have azoospermia as a feature. Our report adds to the completeness of genetic counseling for an individual with azoospermia and congenital cataracts.

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Section: Discussionmentioning

confidence: 99%

A contiguous microdeletion syndrome at Xp23.13 with non-obstructive azoospermia and congenital cataracts

Milunsky

Dong

et al. 2020

J Assist Reprod Genet

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“…This variation was also detected in his grandmother (II-2) with two additional heterozygous variations related to cataracts, namely, the DNMBP c.3410G > A/p.Arg1137Gln on chromosome 10 and the NHS c.350C>G/p.Ala117Gly on chromosome X ( Supplementary Data Sheet 2 ). Considering the previous findings that the DNMBP and NHS are associated with autosomal recessive infantile cataract (Ansar et al, 2018 ) and X-linked congenital cataract (Burdon et al, 2003 ; Ling et al, 2019 ), respectively, and the fact that the DNMBP c.3420G > A and NHS c.350C > G variations were absent from the index patient, we thus chose to focus on the SIPA1L3 c.1871A > G variation for further analysis thereafter.…”

Section: Resultsmentioning

confidence: 90%

Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family

Yang¹,

Zhou

Lin

et al. 2021

Front. Genet.

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The signal-induced proliferation-associated 1-like 3 (SIPA1L3) gene that encodes a putative Rap GTPase-activating protein (RapGAP) has been associated with congenital cataract and eye development abnormalities. However, our current understanding of the mutation spectrum of SIPA1L3 associated with eye defects is limited. By using whole-exome sequencing plus Sanger sequencing validation, we identified a novel heterozygous c.1871A > G (p.Lys624Arg) variation within the predicted RapGAP domain of SIPA1L3 in the proband with isolated juvenile-onset cataracts from a three-generation Chinese family. In this family, the proband's father and grandmother were also heterozygous for the c.1871A > G variation and affected by cataracts varying in morphology, severity, and age of onset. Sequence alignment shows that the Lys 624 residue of SIPA1L3 is conserved across the species. Based on the resolved structure of Rap1–Rap1GAP complex, homology modeling implies that the Lys 624 residue is structurally homologous to the Lys 194 of Rap1GAP, a highly conserved lysine residue that is involved in the interface between Rap1 and Rap1GAP and critical for the affinity to Rap·GTP. We reasoned that arginine substitution of lysine 624 might have an impact on the SIPA1L3-Rap·GTP interaction, thereby affecting the regulatory function of SIPA1L3 on Rap signaling. Collectively, our finding expands the mutation spectrum of SIPA1L3 and provides new clues to the molecular mechanisms of SIPA1L3-related cataracts. Further investigations are warranted to validate the functional alteration of the p.Lys624Arg variant of SIPA1L3.

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“…Traditionally, mutations seen in the NHS gene have been detected using sequencing [ 30 , 31 ]. While this assay is useful in detecting single nucleotide variants and small deletions and insertions (indels), it is not effective at identifying aneuploidy, balanced and unbalanced translocations.…”

Section: Discussionmentioning

confidence: 99%

Allelic and dosage effects of NHS in X-linked cataract and Nance–Horan syndrome: a family study and literature review

et al. 2021

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Nance–Horan syndrome (NHS) is a rare X-linked dominant disorder caused by mutation in the NHS gene on chromosome Xp22.13. (OMIM 302350). Classic NHS manifested in males is characterized by congenital cataracts, dental anomalies, dysmorphic facial features and occasionally intellectual disability. Females typically have a milder presentation. The majority of reported cases of NHS are the result of nonsense mutations and small deletions. Isolated X-linked congenital cataract is caused by non-recurrent rearrangement-associated aberrant NHS transcription. Classic NHS in females associated with gene disruption by balanced X-autosome translocation has been infrequently reported. We present a familial NHS associated with translocation t(X;19) (Xp22.13;q13.1). The proband, a 28-year-old female, presented with intellectual disability, dysmorphic features, short stature, primary amenorrhea, cleft palate, and horseshoe kidney, but no NHS phenotype. A karyotype and chromosome microarray analysis (CMA) revealed partial monosomy Xp/partial trisomy 19q with the breakpoint at Xp22.13 disrupting the NHS gene. Family history revealed congenital cataracts and glaucoma in the patient’s mother, and congenital cataracts in maternal half-sister and maternal grandmother. The same balanced translocation t(X;19) was subsequently identified in both the mother and maternal half-sister, and further clinical evaluation of the maternal half-sister made a diagnosis of NHS. This study describes the clinical implication of NHS gene disruption due to balanced X-autosome translocations as a unique mechanism causing Nance–Horan syndrome, refines dose effects of NHS on disease presentation and phenotype expressivity, and justifies consideration of karyotype and fluorescence in situ hybridization (FISH) analysis for female patients with familial NHS if single-gene analysis of NHS is negative.

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Whole exome sequencing identified a novel truncation mutation in the NHS gene associated with Nance-Horan syndrome

Cited by 13 publications

References 17 publications

A contiguous microdeletion syndrome at Xp23.13 with non-obstructive azoospermia and congenital cataracts

A contiguous microdeletion syndrome at Xp23.13 with non-obstructive azoospermia and congenital cataracts

Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family

Allelic and dosage effects of NHS in X-linked cataract and Nance–Horan syndrome: a family study and literature review

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