Homozygosity stretches around homozygous mutations in autosomal recessive disorders: patients from nonconsanguineous Indian families

Phadke, Shubha R.; Srivastava, Priyanka; Sharma, Pankaj; Rai, Archana; Masih, Suzena

doi:10.1007/s12041-020-01250-6

Cited by 10 publications

(7 citation statements)

References 6 publications

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“…Also, in 13/20 (65%) non‐consanguineous families with a conclusive result, both partners had the same variant, shedding light on the hidden consanguinity due to highly prevalent endogamy and a possible founder effect. Although various studies have hinted at the presence of hidden consanguinity in our population, the exact percentage is not known 4 …”

Section: Discussionmentioning

confidence: 86%

“…Phadke et al. have shown that long stretches of homozygous regions are seen in nonconsanguineous Indian couples due to highly prevalent endogamy, which can cause increased prevalence of rare AR disorders in this population 4 . The recurrence risk for AR disorders in future offsprings is 25%.…”

Section: Introductionmentioning

confidence: 99%

“…3 Phadke et al have shown that long stretches of homozygous regions are seen in nonconsanguineous Indian couples due to highly prevalent endogamy, which can cause increased prevalence of rare AR disorders in this population. 4 The recurrence risk for AR disorders in future offsprings is 25%. Exome sequencing of parents can be done to search for carrier status of genetic diseases with AR or X-linked recessive inheritance to identify the pathogenic/likely pathogenic variants (P/LP) in genes related to the phenotype in a deceased child.…”

Section: Introductionmentioning

confidence: 99%

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Retrospective diagnosis by parental testing in the next generation sequencing era and utility of reanalysis of exome data

et al. 2023

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Objective: Genetic diseases are an important cause of neonatal and childhood mortality. For couples with a history of demise of previous children, screening for carrier status can be done by exome sequencing (ES) of the parents. Our aim was to describe the clinical utility of "targeted parental ES" in such couples and to assess the utility of reanalysis of parental ES data. Method:We analyzed previous records, including ES reports, of 52 families with demise of previous offspring with a suspected genetic disorder. We also retrieved and reanalyzed raw data of parental ES in FASTQ format from the testing lab.Results: A potential diagnosis was obtained in 30/52 (57.7%) of couples. We found 38/70 (54.3%) novel variants in this cohort. Shared carrier status for more than one autosomal or X-linked recessive disorder was identified in 18% of couples. Reanalysis of raw data resulted in a reclassification of variants in 15% of cases. Conclusion:Targeted parental ES can be helpful for families with demise of previous offspring with a suspected genetic disorder. Key pointsWhat's already known about the topic? � Many genetic disorders can be rapidly identified by exome sequencing (ES), but this is not always done early in the course of illness due to cost constraints, and many children succumb to the illness before a molecular diagnosis is made.� ES of parents in such cases has a reported diagnostic yield of 38%-64%. What does this study add?� Parental ES had a diagnostic yield of 57.7%, supporting its usefulness for the evaluation of couples with a history of previous loss of offsprings due to a suspected genetic disorder.� Shared carrier status for more than one autosomal or X-linked recessive disorder was found in 18%, suggesting this should be considered with parental ES.� Reanalysis of parental exome data resulted in reclassification of variants in ~15%.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Retrospective diagnosis by parental testing in the next generation sequencing era and utility of reanalysis of exome data

et al. 2023

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“…For example, in mucopolysaccharidosis I, 54.6% of probands were from nonconsanguineous family [32], and for MONA, all probands were from nonconsanguineous family [33]. Recently, a large ROH around homozygous mutations in autosomal recessive disorders has been reported in Indian nonconsanguineous families [34]. This suggests that the homozygous pathogenic variants in nonconsanguineous parents have probably originated from a founder ancestor.…”

Section: Discussionmentioning

confidence: 99%

Large Region of Homozygous (ROH) Identified in Indian Patients with Autosomal Recessive Limb-Girdle Muscular Dystrophy with p.Thr182Pro Variant in SGCB Gene

Manjunath

Thenral

Lakshmi³

et al. 2023

Human Mutation

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The sarcoglycanopathies are autosomal recessive limb-girdle muscular dystrophies (LGMDs) caused by the mutations in genes encoding the α, β, γ, and δ proteins which stabilizes the sarcolemma of muscle cells. The clinical phenotype is characterized by progressive proximal muscle weakness with childhood onset. Muscle biopsy findings are diagnostic in confirming dystrophic changes and deficiency of one or more sarcoglycan proteins. In this study, we summarized 1,046 LGMD patients for which a precise diagnosis was identified using targeted sequencing. The most frequent phenotypes identified in the patients are LGMDR1 (19.7%), LGMDR4 (19.0%), LGMDR2 (17.5%), and MMD1 (14.5%). Among the reported genes, each of CAPN3, SGCB, and DYSF variants was reported in more than 10% of our study cohort. The most common variant SGCB p.Thr182Pro was identified in 146 (12.5%) of the LGMD patients, and in 97.9% of these patients, the variant was found to be homozygous. To understand the genetic structure of the patients carrying SGCB p.Thr182Pro, we genotyped 68 LGMD patients using a whole genome microarray. Analysis of the array data identified a large ~1 Mb region of homozygosity (ROH) (chr4:51817441-528499552) suggestive of a shared genomic region overlapping the recurrent missense variant and shared across all 68 patients. Haplotype analysis identified 133 marker haplotypes that were present in ~85.3% of the probands as a double allele and absent in all random controls. We also identified 5 markers (rs1910739, rs6852236, rs13122418, rs13353646, and rs6554360) which were present in a significantly higher proportion in the patients compared to random control set ( n = 128 ) and the population database. Of note, admixture analysis was suggestive of greater proportion of West Eurasian/European ancestry as compared to random controls. Haplotype analysis and frequency in the population database indicate a probable event of founder effect. Further systematic study is needed to identify the communities and regions where the SGCB p.Thr182Pro variant is observed in higher proportions. After identifying these communities and//or region, a screening program is needed to identify carriers and provide them counselling.

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“…SNX14 mRNA is highly expressed in the granule and Purkinje cell layer of the cerebellum and the transcript level continues to increase through postnatal life until adulthood, thus explaining the susceptibility of the organ to insult (Thomas et al, 2014). The identification of a homozygous variant for this rare autosomal recessive disorder in a non‐consanguineous Indian family highlights the system of marriages between same groups and effects of inbreeding (Phadke et al, 2021). The gene has no specific hot spot and the majority of reported variants were nonsense and frameshift variants.…”

Section: Discussionmentioning

confidence: 99%

Autosomal recessive spinocerebellar ataxia‐20 due to a novel SNX14 variant in an Indian girl

Sait

Moirangthem

Agrawal

et al. 2022

American J of Med Genetics Pt A

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Autosomal recessive spinocerebellar ataxia-20 is a rare disorder having distinctive coarse facies in addition to intellectual disability and cerebellar ataxia, with less than 35 cases reported worldwide. It is caused by biallelic variants in the SNX14 gene and is classified under the group of autophagy disorders. We report a 9-year-old girl who presented with classic clinical features of autosomal recessive spinocerebellar ataxia-20 and cerebellar atrophy on magnetic resonance imaging of brain. Trio exome sequencing with Sanger confirmation revealed a novel splice site variant, c.140 + 3A > T in the SNX14 gene. The variant pathogenicity established by mRNA expression study showed a significant reduction in the expression levels of SNX14 gene in proband and her parents on comparison to the control. The electron microscopy of the skin fibroblasts of proband depicted numerous cytoplasmic vacuoles with variable degrees of dense staining material. In addition, we have briefly reviewed and compared the phenotypic features of published cases of autosomal recessive spinocerebellar ataxia-20 in the literature. Coarse facies, intellectual disability with severe speech delay, hypotonia, and cerebellar atrophy were universal findings in the published cases. This is the second reported case from the Indian subcontinent.

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Homozygosity stretches around homozygous mutations in autosomal recessive disorders: patients from nonconsanguineous Indian families

Cited by 10 publications

References 6 publications

Retrospective diagnosis by parental testing in the next generation sequencing era and utility of reanalysis of exome data

Retrospective diagnosis by parental testing in the next generation sequencing era and utility of reanalysis of exome data

Large Region of Homozygous (ROH) Identified in Indian Patients with Autosomal Recessive Limb-Girdle Muscular Dystrophy with p.Thr182Pro Variant in SGCB Gene

Autosomal recessive spinocerebellar ataxia‐20 due to a novel SNX14 variant in an Indian girl

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