Phenotypic diversity and genetic complexity of <scp><i>PAX3</i></scp>‐related Waardenburg syndrome

Somashekar, Puneeth H.; Upadhyai, Priyanka; Narayanan, Dhanya Lakshmi; Kamath, Nutan; Bajaj, Shruti; Girisha, Katta M.; Shukla, Anju

doi:10.1002/ajmg.a.61893

Cited by 8 publications

(6 citation statements)

References 34 publications

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“…By targeted NGS, we identified candidate pathogenic variants in each of the multiplex, autosomal dominant families, including c.580G > A in EYA4 for Family A, c.1616+3A > T in EYA4 for Family B, c.991-15_991-13del in DFNA5 for Family C, and c.322-57_322-8del in PAX3 for Family D. Cosegregation of the variants and the disease phenotype were confirmed in all participating family members (Figure 1). The audiograms and associating features (the vestibular disorder) in Family C and the WS3-associated phenotype in Family D are consistent with previously reported genotype-phenotype correlation for the corresponding genes (Somashekar et al, 2020). In the two simplex families, compound heterozygous variants c.5426+1G > A and c.6087-3T > G in PTPRQ were identified in the proband of Family E and homozygous variant c.164+5G > A in USH1G in Family F. No other candidate variants in known deafness genes have been identified.…”

Section: Identification and Verification Of The Candidate Pathogenic Variantssupporting

confidence: 90%

Detection and Functional Verification of Noncanonical Splice Site Mutations in Hereditary Deafness

et al. 2021

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Splice site mutations contribute to a significant portion of the genetic causes for mendelian disorders including deafness. By next-generation sequencing of 4 multiplex, autosomal dominant families and 2 simplex, autosomal recessive families with hereditary deafness, we identified a variety of candidate pathogenic variants in noncanonical splice sites of known deafness genes, which include c.1616+3A > T and c.580G > A in EYA4, c.322-57_322-8del in PAX3, c.991-15_991-13del in DFNA5, c.6087-3T > G in PTPRQ and c.164+5G > A in USH1G. All six variants were predicted to affect the RNA splicing by at least one of the computational tools Human Splicing Finder, NNSPLICE and NetGene2. Phenotypic segregation of the variants was confirmed in all families and is consistent with previously reported genotype-phenotype correlations of the corresponding genes. Minigene analysis showed that those splicing site variants likely have various negative impact including exon-skipping (c.1616+3A > T and c.580G > A in EYA4, c.991-15_991-13del in DFNA5), intron retention (c.322-57_322-8del in PAX3), exon skipping and intron retention (c.6087-3T > G in PTPRQ) and shortening of exon (c.164+5G > A in USH1G). Our study showed that the cryptic, noncanonical splice site mutations may play an important role in the molecular etiology of hereditary deafness, whose diagnosis can be facilitated by modified filtering criteria for the next-generation sequencing data, functional verification, as well as segregation, bioinformatics, and genotype-phenotype correlation analysis.

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Section: Identification and Verification Of The Candidate Pathogenic Variantssupporting

confidence: 90%

Detection and Functional Verification of Noncanonical Splice Site Mutations in Hereditary Deafness

et al. 2021

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“…In two families (F3 and F4), though parents carried MGVs, only a single Mendelian disorder was observed in different individuals in the family. The details of F8, F9 and F10 were published previously [ 12 , 13 ]. Consanguinity was present in eight (8/14, 57.1%) of them.…”

Section: Resultsmentioning

confidence: 99%

Multilocus disease-causing genomic variations for Mendelian disorders: role of systematic phenotyping and implications on genetic counselling

et al. 2021

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Multilocus disease-causing genomic variations (MGVs) and multiple genetic diagnoses (MGDs) are increasingly being recognised in individuals and families with Mendelian disorders. This can be mainly attributed to the widespread use of genomic tests for the evaluation of these disorders. We conducted a retrospective study of families evaluated over the last 6 years at our centre to identify families with MGVs and MGDs. MGVs were observed in fourteen families. We observed five different consequences: (i) individuals with MGVs presenting as blended phenotypes (ii) individuals with MGVs presenting with distinct phenotypes (iii) individuals with MGVs with age-dependent penetrance (iv) individuals with MGVs with one phenotype obscured by another more predominant phenotype (v) two distinct phenotypes in different individuals in families with MGVs. Consanguinity was present in eight (8/14, 57.1%) of them. Thirteen families had two Mendelian disorders and one had three Mendelian disorders. The risk of recurrence of one or more conditions in these families ranged from 25% to 75%. Our findings underline the importance of the role of a clinical geneticist in systematic phenotyping, challenges in genetic counselling and risk estimation in families with MGVs and MGDs, especially in highly inbred populations.

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“…There was near absence of myelination in the proband, features indicating an insult to the early developing brain, starting from intra-uterine life itself. The timing coincides with activity of the neutral sphingomyelinases, particularly n-SMase3 whose function has been demonstrated to be its highest in the early stages of brain development [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…[ 9 ] Exome based pairwise kinship analysis was performed to check for relatedness between the parents using KING.11 with kinship co-efficient cut-off of 0.0884. Quantitative PCR (qPCR) was on genomic DNA of the proband, clinically normal parents and two unrelated healthy controls as previously described [ 10 ]. Detailed methodology is provided in s supplementary section .…”

Section: Methodsmentioning

confidence: 99%

Growth and neurodevelopmental disorder with arthrogryposis, microcephaly and structural brain anomalies caused by Bi-allelic partial deletion of SMPD4 gene

et al. 2021

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Neutral sphingomyelinases have an important role in generation of ceramide and phosphorylcholine from sphingomyelins which then act as secondary messengers in various signaling pathways of the cellular machinery. They function ubiquitously with a predominant role in the central nervous system. Neutral sphingomyelinase type 3, encoded by SMPD4 gene has recently been reported to cause a severe autosomal recessive neurodevelopmental disorder with congenital arthrogryposis and microcephaly. We report a 22-month-old girl having characteristic features of neurodevelopmental delay, prenatal onset growth failure, arthrogryposis, microcephaly and brain anomalies including severe hypomyelination, simplified gyral pattern and hypoplasia of corpus callosum and brainstem. Additionally, she was noted to have nystagmus and visual impairment secondary to macular dystrophy and retinal pigment epithelial stippling at posterior pole. Copy number variant analysis from trio whole exome sequencing (ES) enabled identification of a homozygous 11kb deletion encompassing exons 18 −20 of SMPD 4 gene, confirming the diagnosis of SMPD4-related disorder in her.

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Phenotypic diversity and genetic complexity of PAX3‐related Waardenburg syndrome

Cited by 8 publications

References 34 publications

Detection and Functional Verification of Noncanonical Splice Site Mutations in Hereditary Deafness

Detection and Functional Verification of Noncanonical Splice Site Mutations in Hereditary Deafness

Multilocus disease-causing genomic variations for Mendelian disorders: role of systematic phenotyping and implications on genetic counselling

Growth and neurodevelopmental disorder with arthrogryposis, microcephaly and structural brain anomalies caused by Bi-allelic partial deletion of SMPD4 gene

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