ClinVar Genomic variation as it relates to human health

Neuronal Intranuclear Inclusion Disease In affected members of 9 unrelated Japanese families with neuronal intranuclear inclusion disease (NIID; 603472) and in 40 Japanese patients with sporadic NIID, Sone et al. (2019) identified a heterozygous trinucleotide repeat expansion (GGC) in the 5-prime untranslated region of the NOTCH2NLC gene. The mutation, which was found by a combination of linkage analysis, long-read whole-genome sequencing, and a specific protocol to detect tandem repeats, segregated with the disorder in all families. The repeat number in a total of 63 patients ranged from 71 to 183, and the repeat number among 225 controls ranged from 6 to 30, although 1 control had 61 repeats and may have been a presymptomatic carrier. RNA analysis of NOTCH2NLC in fibroblasts derived from 2 patients from 1 family showed normal expression levels, but abnormal anti-sense transcripts and evidence of differentially expressed genes. However, there was no difference in methylation of a CpG island immediately downstream of the repeat. Independently and simultaneously, Ishiura et al. (2019) identified a heterozygous expanded CGG repeat in the 5-prime untranslated sequence of the NOTCH2NLC gene in 12 probands from 12 unrelated Japanese families with NIID and in 14 Japanese patients with sporadic NIID. The abnormal expansions segregated with the disorders in 3 families who were studied in detail. The repeat expansion was also identified in 2 Malaysian males of Chinese descent with the disorder. The number of CGG repeat units among patients ranged from 90 to 180, whereas the number of repeat units in over 1,000 controls ranged from 7 to 43. The authors observed intergenerational instability of expanded repeats in 2 parent-offspring pairs, although genetic anticipation could not be confirmed. Noting the phenotypic overlap with other expanded trinucleotide repeat disorders, mainly FXTAS (300623), Ishiura et al. (2019) hypothesized that NIID is also caused by an expanded trinucleotide repeat. The authors used whole-genome sequencing data from the NIID patients and applied a software program to analyze short reads for abnormal tandem repeats. The identified tandem repeat expansions in the NOTCH2NLC gene were confirmed by RP-PCR, Southern blot, and long-read sequence analysis. Examination of the expanded sequence from 1 patient suggested that the expanded CGG repeat was hypermethylated; however, there was no difference between RNA transcript levels of 3 patients compared to 8 controls. (Ishiura et al. (2019) indicated that the NOTCH2NLC and NBPF19 (614006) genes are identical, but Scott (2019) stated that the genes are distinct and that the repeat occurs in the NOTCH2NLC gene.) Tian et al. (2019) identified a heterozygous GGC repeat expansion in the NOTCH2NLC gene in affected members of 4 unrelated Chinese NIID families and in 5 patients with sporadic NIID. The variant in the first family, which was a 5-generation family, was found by a combination of linkage analysis and long-read genome sequencing and confirmed by PCR analysis. The expanded repeat segregated with the disorder in the families. Subsequently, 3 additional families with a diagnosis of Parkinson disease and 2 additional families with a diagnosis of Alzheimer disease were identified by long-range sequencing, bringing the total to 9 unrelated families. The repeat size among 211 healthy controls ranged from 5 to 38, with nodes at 11 and 16 repeats, whereas all familial patients and patients with sporadic disease had repeats larger than 66 (range 66 to 517). The number of GGC repeats in the muscle weakness-predominant phenotypic subtype ranged from 118 to 517; the repeat size in the parkinsonism-dominant subgroup ranged from 66 to 102; and the repeat size in the dementia-dominant subtype ranged from 91 to 268. There was no significant difference in methylation pattern or expression of NOTCH2NLC between controls and patients, suggesting that the expanded repeat may be pathogenic at the RNA level. Hereditary Essential Tremor 6 In affected members of 11 Chinese families with hereditary essential tremor-6 (ETM6; 618866), Sun et al. (2020) identified a heterozygous GGC repeat expansion in the 5-prime untranslated region of the NOTCH2NLC gene. The authors first identified the mutation in affected members of 2 families by a combination of linkage analysis and long-read genome sequencing after whole-exome sequencing failed to identify a candidate gene. The expansion, which was confirmed by repeat-primed PCR, segregated with the disorder in both families. Similar assays performed on 195 additional families with an ETM phenotype identified 9 other families with the same genetic abnormality, yielding a frequency of 5.58% among all families. The GGC repeat sizes of patients from the 11 families ranged from 60 to 250 (average of 118), whereas unaffected family members carried normal repeats, ranging from 6 to 23 (average of 14). Among 1,305 controls, the repeats ranged from 4 to 41 (average of 16). Functional studies of the variant were not performed. Oculopharyngodistal Myopathy 3 In 7 unrelated Japanese patients with oculopharyngodistal myopathy-3 (OPDM3; 619473), Ogasawara et al. (2020) identified heterozygous CGG trinucleotide repeat expansions in the noncoding region of the NOTCH2NLC gene. The number of repeats in the patients was over 100, and 1 patient (P2) had 2 expansions of 217 and 674 repeats. However, she did not have a more severe phenotype, precluding genotype/phenotype correlations. Functional studies of the variants and studies of patient cells were not performed. In 5 Chinese patients, including 2 sibs, with OPDM3, Yu et al. (2021) identified heterozygous trinucleotide GGC repeat expansions in the 5-prime untranslated region (UTR) of the NOTCH2NLC gene. The expansions were found by long-range sequencing. One of the patients had a similarly affected sister; the other cases were sporadic. The repeat size, determined in all but 1 patient, ranged from 128 to 198 repeats, whereas it ranged from 6 to 26 repeats among normal Chinese controls. Long-range sequencing performed in 8 asymptomatic individuals from 3 of the families showed that 3 asymptomatic members had repeat counts of more than 400, whereas 5 other asymptomatic family members had normal-sized alleles. RT-PCR studies showed that NOTCH2NLC mRNA levels were increased in muscle, but not blood, of OPDM3 patients. Studies of patient muscle tissue and HEK293 cells expressing a pathogenic expanded trinucleotide repeat indicated that mutant NOTCH2NLC polyG proteins formed toxic aggregates that induced cell death. The mutant protein colocalized with p62 (SQSTM1; 601530) and 2 RNA-binding proteins within intranuclear inclusions in patient muscle samples. Methylation analysis showed that methylation of the NOTCH2NLC gene was unaltered in patients, but increased significantly in asymptomatic carriers. The authors postulated a toxic gain-of-function effect with alterations in RNA for the pathogenesis of OPDM3. The 4 probands were ascertained from a cohort of 24 OPDM patients who underwent genetic analysis; NOTCH2NLC expansions accounted for 16.67%. (less)

Neuronal Intranuclear Inclusion Disease In affected members of 9 unrelated Japanese families with neuronal intranuclear inclusion disease (NIID; 603472) and in 40 Japanese patients with sporadic NIID, Sone et al. (2019) identified a heterozygous trinucleotide repeat expansion (GGC) in the 5-prime untranslated region of the NOTCH2NLC gene. The mutation, which was found by a combination of linkage analysis, long-read whole-genome sequencing, and a specific protocol to detect tandem repeats, segregated with the disorder in all families. The repeat number in a total of 63 patients ranged from 71 to 183, and the repeat number among 225 controls ranged from 6 to 30, although 1 control had 61 repeats and may have been a presymptomatic carrier. RNA analysis of NOTCH2NLC in fibroblasts derived from 2 patients from 1 family showed normal expression levels, but abnormal anti-sense transcripts and evidence of differentially expressed genes. However, there was no difference in methylation of a CpG island immediately downstream of the repeat. Independently and simultaneously, Ishiura et al. (2019) identified a heterozygous expanded CGG repeat in the 5-prime untranslated sequence of the NOTCH2NLC gene in 12 probands from 12 unrelated Japanese families with NIID and in 14 Japanese patients with sporadic NIID. The abnormal expansions segregated with the disorders in 3 families who were studied in detail. The repeat expansion was also identified in 2 Malaysian males of Chinese descent with the disorder. The number of CGG repeat units among patients ranged from 90 to 180, whereas the number of repeat units in over 1,000 controls ranged from 7 to 43. The authors observed intergenerational instability of expanded repeats in 2 parent-offspring pairs, although genetic anticipation could not be confirmed. Noting the phenotypic overlap with other expanded trinucleotide repeat disorders, mainly FXTAS (300623), Ishiura et al. (2019) hypothesized that NIID is also caused by an expanded trinucleotide repeat. The authors used whole-genome sequencing data from the NIID patients and applied a software program to analyze short reads for abnormal tandem repeats. The identified tandem repeat expansions in the NOTCH2NLC gene were confirmed by RP-PCR, Southern blot, and long-read sequence analysis. Examination of the expanded sequence from 1 patient suggested that the expanded CGG repeat was hypermethylated; however, there was no difference between RNA transcript levels of 3 patients compared to 8 controls. (Ishiura et al. (2019) indicated that the NOTCH2NLC and NBPF19 (614006) genes are identical, but Scott (2019) stated that the genes are distinct and that the repeat occurs in the NOTCH2NLC gene.) Tian et al. (2019) identified a heterozygous GGC repeat expansion in the NOTCH2NLC gene in affected members of 4 unrelated Chinese NIID families and in 5 patients with sporadic NIID. The variant in the first family, which was a 5-generation family, was found by a combination of linkage analysis and long-read genome sequencing and confirmed by PCR analysis. The expanded repeat segregated with the disorder in the families. Subsequently, 3 additional families with a diagnosis of Parkinson disease and 2 additional families with a diagnosis of Alzheimer disease were identified by long-range sequencing, bringing the total to 9 unrelated families. The repeat size among 211 healthy controls ranged from 5 to 38, with nodes at 11 and 16 repeats, whereas all familial patients and patients with sporadic disease had repeats larger than 66 (range 66 to 517). The number of GGC repeats in the muscle weakness-predominant phenotypic subtype ranged from 118 to 517; the repeat size in the parkinsonism-dominant subgroup ranged from 66 to 102; and the repeat size in the dementia-dominant subtype ranged from 91 to 268. There was no significant difference in methylation pattern or expression of NOTCH2NLC between controls and patients, suggesting that the expanded repeat may be pathogenic at the RNA level. Hereditary Essential Tremor 6 In affected members of 11 Chinese families with hereditary essential tremor-6 (ETM6; 618866), Sun et al. (2020) identified a heterozygous GGC repeat expansion in the 5-prime untranslated region of the NOTCH2NLC gene. The authors first identified the mutation in affected members of 2 families by a combination of linkage analysis and long-read genome sequencing after whole-exome sequencing failed to identify a candidate gene. The expansion, which was confirmed by repeat-primed PCR, segregated with the disorder in both families. Similar assays performed on 195 additional families with an ETM phenotype identified 9 other families with the same genetic abnormality, yielding a frequency of 5.58% among all families. The GGC repeat sizes of patients from the 11 families ranged from 60 to 250 (average of 118), whereas unaffected family members carried normal repeats, ranging from 6 to 23 (average of 14). Among 1,305 controls, the repeats ranged from 4 to 41 (average of 16). Functional studies of the variant were not performed. Oculopharyngodistal Myopathy 3 In 7 unrelated Japanese patients with oculopharyngodistal myopathy-3 (OPDM3; 619473), Ogasawara et al. (2020) identified heterozygous CGG trinucleotide repeat expansions in the noncoding region of the NOTCH2NLC gene. The number of repeats in the patients was over 100, and 1 patient (P2) had 2 expansions of 217 and 674 repeats. However, she did not have a more severe phenotype, precluding genotype/phenotype correlations. Functional studies of the variants and studies of patient cells were not performed. In 5 Chinese patients, including 2 sibs, with OPDM3, Yu et al. (2021) identified heterozygous trinucleotide GGC repeat expansions in the 5-prime untranslated region (UTR) of the NOTCH2NLC gene. The expansions were found by long-range sequencing. One of the patients had a similarly affected sister; the other cases were sporadic. The repeat size, determined in all but 1 patient, ranged from 128 to 198 repeats, whereas it ranged from 6 to 26 repeats among normal Chinese controls. Long-range sequencing performed in 8 asymptomatic individuals from 3 of the families showed that 3 asymptomatic members had repeat counts of more than 400, whereas 5 other asymptomatic family members had normal-sized alleles. RT-PCR studies showed that NOTCH2NLC mRNA levels were increased in muscle, but not blood, of OPDM3 patients. Studies of patient muscle tissue and HEK293 cells expressing a pathogenic expanded trinucleotide repeat indicated that mutant NOTCH2NLC polyG proteins formed toxic aggregates that induced cell death. The mutant protein colocalized with p62 (SQSTM1; 601530) and 2 RNA-binding proteins within intranuclear inclusions in patient muscle samples. Methylation analysis showed that methylation of the NOTCH2NLC gene was unaltered in patients, but increased significantly in asymptomatic carriers. The authors postulated a toxic gain-of-function effect with alterations in RNA for the pathogenesis of OPDM3. The 4 probands were ascertained from a cohort of 24 OPDM patients who underwent genetic analysis; NOTCH2NLC expansions accounted for 16.67%. (less)

Neuronal Intranuclear Inclusion Disease In affected members of 9 unrelated Japanese families with neuronal intranuclear inclusion disease (NIID; 603472) and in 40 Japanese patients with sporadic NIID, Sone et al. (2019) identified a heterozygous trinucleotide repeat expansion (GGC) in the 5-prime untranslated region of the NOTCH2NLC gene. The mutation, which was found by a combination of linkage analysis, long-read whole-genome sequencing, and a specific protocol to detect tandem repeats, segregated with the disorder in all families. The repeat number in a total of 63 patients ranged from 71 to 183, and the repeat number among 225 controls ranged from 6 to 30, although 1 control had 61 repeats and may have been a presymptomatic carrier. RNA analysis of NOTCH2NLC in fibroblasts derived from 2 patients from 1 family showed normal expression levels, but abnormal anti-sense transcripts and evidence of differentially expressed genes. However, there was no difference in methylation of a CpG island immediately downstream of the repeat. Independently and simultaneously, Ishiura et al. (2019) identified a heterozygous expanded CGG repeat in the 5-prime untranslated sequence of the NOTCH2NLC gene in 12 probands from 12 unrelated Japanese families with NIID and in 14 Japanese patients with sporadic NIID. The abnormal expansions segregated with the disorders in 3 families who were studied in detail. The repeat expansion was also identified in 2 Malaysian males of Chinese descent with the disorder. The number of CGG repeat units among patients ranged from 90 to 180, whereas the number of repeat units in over 1,000 controls ranged from 7 to 43. The authors observed intergenerational instability of expanded repeats in 2 parent-offspring pairs, although genetic anticipation could not be confirmed. Noting the phenotypic overlap with other expanded trinucleotide repeat disorders, mainly FXTAS (300623), Ishiura et al. (2019) hypothesized that NIID is also caused by an expanded trinucleotide repeat. The authors used whole-genome sequencing data from the NIID patients and applied a software program to analyze short reads for abnormal tandem repeats. The identified tandem repeat expansions in the NOTCH2NLC gene were confirmed by RP-PCR, Southern blot, and long-read sequence analysis. Examination of the expanded sequence from 1 patient suggested that the expanded CGG repeat was hypermethylated; however, there was no difference between RNA transcript levels of 3 patients compared to 8 controls. (Ishiura et al. (2019) indicated that the NOTCH2NLC and NBPF19 (614006) genes are identical, but Scott (2019) stated that the genes are distinct and that the repeat occurs in the NOTCH2NLC gene.) Tian et al. (2019) identified a heterozygous GGC repeat expansion in the NOTCH2NLC gene in affected members of 4 unrelated Chinese NIID families and in 5 patients with sporadic NIID. The variant in the first family, which was a 5-generation family, was found by a combination of linkage analysis and long-read genome sequencing and confirmed by PCR analysis. The expanded repeat segregated with the disorder in the families. Subsequently, 3 additional families with a diagnosis of Parkinson disease and 2 additional families with a diagnosis of Alzheimer disease were identified by long-range sequencing, bringing the total to 9 unrelated families. The repeat size among 211 healthy controls ranged from 5 to 38, with nodes at 11 and 16 repeats, whereas all familial patients and patients with sporadic disease had repeats larger than 66 (range 66 to 517). The number of GGC repeats in the muscle weakness-predominant phenotypic subtype ranged from 118 to 517; the repeat size in the parkinsonism-dominant subgroup ranged from 66 to 102; and the repeat size in the dementia-dominant subtype ranged from 91 to 268. There was no significant difference in methylation pattern or expression of NOTCH2NLC between controls and patients, suggesting that the expanded repeat may be pathogenic at the RNA level. Hereditary Essential Tremor 6 In affected members of 11 Chinese families with hereditary essential tremor-6 (ETM6; 618866), Sun et al. (2020) identified a heterozygous GGC repeat expansion in the 5-prime untranslated region of the NOTCH2NLC gene. The authors first identified the mutation in affected members of 2 families by a combination of linkage analysis and long-read genome sequencing after whole-exome sequencing failed to identify a candidate gene. The expansion, which was confirmed by repeat-primed PCR, segregated with the disorder in both families. Similar assays performed on 195 additional families with an ETM phenotype identified 9 other families with the same genetic abnormality, yielding a frequency of 5.58% among all families. The GGC repeat sizes of patients from the 11 families ranged from 60 to 250 (average of 118), whereas unaffected family members carried normal repeats, ranging from 6 to 23 (average of 14). Among 1,305 controls, the repeats ranged from 4 to 41 (average of 16). Functional studies of the variant were not performed. Oculopharyngodistal Myopathy 3 In 7 unrelated Japanese patients with oculopharyngodistal myopathy-3 (OPDM3; 619473), Ogasawara et al. (2020) identified heterozygous CGG trinucleotide repeat expansions in the noncoding region of the NOTCH2NLC gene. The number of repeats in the patients was over 100, and 1 patient (P2) had 2 expansions of 217 and 674 repeats. However, she did not have a more severe phenotype, precluding genotype/phenotype correlations. Functional studies of the variants and studies of patient cells were not performed. In 5 Chinese patients, including 2 sibs, with OPDM3, Yu et al. (2021) identified heterozygous trinucleotide GGC repeat expansions in the 5-prime untranslated region (UTR) of the NOTCH2NLC gene. The expansions were found by long-range sequencing. One of the patients had a similarly affected sister; the other cases were sporadic. The repeat size, determined in all but 1 patient, ranged from 128 to 198 repeats, whereas it ranged from 6 to 26 repeats among normal Chinese controls. Long-range sequencing performed in 8 asymptomatic individuals from 3 of the families showed that 3 asymptomatic members had repeat counts of more than 400, whereas 5 other asymptomatic family members had normal-sized alleles. RT-PCR studies showed that NOTCH2NLC mRNA levels were increased in muscle, but not blood, of OPDM3 patients. Studies of patient muscle tissue and HEK293 cells expressing a pathogenic expanded trinucleotide repeat indicated that mutant NOTCH2NLC polyG proteins formed toxic aggregates that induced cell death. The mutant protein colocalized with p62 (SQSTM1; 601530) and 2 RNA-binding proteins within intranuclear inclusions in patient muscle samples. Methylation analysis showed that methylation of the NOTCH2NLC gene was unaltered in patients, but increased significantly in asymptomatic carriers. The authors postulated a toxic gain-of-function effect with alterations in RNA for the pathogenesis of OPDM3. The 4 probands were ascertained from a cohort of 24 OPDM patients who underwent genetic analysis; NOTCH2NLC expansions accounted for 16.67%. (less)