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Novel PEX1 mutations in fibroblasts from children with Zellweger spectrum disorders exhibit temperature sensitive characteristics

Liang JS, Hung KL, Lin LJ, Ong WP, Keng WT, Lu JF

Epilepsy Behav, 2023 Aug;145:109266.
PMID: 37385119 DOI: 10.1016/j.yebeh.2023.109266

Zellweger spectrum disorders (ZSD) are rare autosomal recessive disorders caused by defects in peroxisome biogenesis factor (PEX; peroxin) genes leading to impaired transport of peroxisomal proteins with peroxisomal targeting signals (PTS). Four patients, including a pair of homozygotic twins, diagnosed as ZSD by genetic study with different clinical presentations and outcomes as well as various novel mutations are described here. A total of 3 novel mutations, including a nonsense, a frameshift, and a splicing mutation, in PEX1 from ZSD patients were identified and unequivocally confirmed that the p.Ile989Thr mutant PEX1 exhibited temperature-sensitive characteristics and is associated with milder ZSD. The nature of the p.Ile989Thr mutant exhibited different characteristics from that of the other previously identified temperature-sensitive p.Gly843Asp PEX1 mutant. Transcriptome profiles under nonpermissive vs. permissive conditions were explored to facilitate the understanding of p.Ile989Thr mutant PEX1. Further investigation of molecular mechanisms may help to clarify potential genetic causes that could modify the clinical presentation of ZSD.
Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies

McInerney-Leo AM, Harris JE, Leo PJ, Marshall MS, Gardiner B, Kinning E, et al.

Clin Genet, 2015 Dec;88(6):550-7.
PMID: 25492405 DOI: 10.1111/cge.12550

Short-rib thoracic dystrophies (SRTDs) are congenital disorders due to defects in primary cilium function. SRTDs are recessively inherited with mutations identified in 14 genes to date (comprising 398 exons). Conventional mutation detection (usually by iterative Sanger sequencing) is inefficient and expensive, and often not undertaken. Whole exome massive parallel sequencing has been used to identify new genes for SRTD (WDR34, WDR60 and IFT172); however, the clinical utility of whole exome sequencing (WES) has not been established. WES was performed in 11 individuals with SRTDs. Compound heterozygous or homozygous mutations were identified in six confirmed SRTD genes in 10 individuals (IFT172, DYNC2H1, TTC21B, WDR60, WDR34 and NEK1), giving overall sensitivity of 90.9%. WES data from 993 unaffected individuals sequenced using similar technology showed two individuals with rare (minor allele frequency <0.005) compound heterozygous variants of unknown significance in SRTD genes (specificity >99%). Costs for consumables, laboratory processing and bioinformatic analysis were
Hyperexcretion of homocitrulline in a Malaysian patient with lysinuric protein intolerance

Habib A, Md Yunus Z, Azize NA, Ch'ng GS, Ong WP, Chen BC, et al.

Eur J Pediatr, 2013 Sep;172(9):1277-81.
PMID: 23358709 DOI: 10.1007/s00431-013-1947-1

Lysinuric protein intolerance (LPI; MIM 222700) is an inherited aminoaciduria with an autosomal recessive mode of inheritance. Biochemically, affected patients present with increased excretion of the cationic amino acids: lysine, arginine, and ornithine. We report the first case of LPI diagnosed in Malaysia presented with excessive excretion of homocitrulline. The patient was a 4-year-old male who presented with delayed milestones, recurrent diarrhea, and severe failure to thrive. He developed hyperammonemic coma following a forced protein-rich diet. Plasma amino acid analysis showed increased glutamine, alanine, and citrulline but decreased lysine, arginine and ornithine. Urine amino acids showed a marked excretion of lysine and ornithine together with a large peak of unknown metabolite which was subsequently identified as homocitrulline by tandem mass spectrometry. Molecular analysis confirmed a previously unreported homozygous mutation at exon 1 (235 G > A, p.Gly79Arg) in the SLC7A7 gene. This report demonstrates a novel mutation in the SLC7A7 gene in this rare inborn error of diamino acid metabolism. It also highlights the importance of early and efficient treatment of infections and dehydration in these patients.
CONCLUSION: The diagnosis of LPI is usually not suspected by clinical findings alone, and specific laboratory investigations and molecular analysis are important to get a definitive diagnosis.
Fulltext Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay

Saitsu H, Watanabe M, Akita T, Ohba C, Sugai K, Ong WP, et al.

Sci Rep, 2016 07 20;6:30072.
PMID: 27436767 DOI: 10.1038/srep30072

Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the early-onset epileptic syndromes characterized by migrating polymorphous focal seizures. Whole exome sequencing (WES) in ten sporadic and one familial case of EIMFS revealed compound heterozygous SLC12A5 (encoding the neuronal K(+)-Cl(-) co-transporter KCC2) mutations in two families: c.279 + 1G > C causing skipping of exon 3 in the transcript (p.E50_Q93del) and c.572 C >T (p.A191V) in individuals 1 and 2, and c.967T > C (p.S323P) and c.1243 A > G (p.M415V) in individual 3. Another patient (individual 4) with migrating multifocal seizures and compound heterozygous mutations [c.953G > C (p.W318S) and c.2242_2244del (p.S748del)] was identified by searching WES data from 526 patients and SLC12A5-targeted resequencing data from 141 patients with infantile epilepsy. Gramicidin-perforated patch-clamp analysis demonstrated strongly suppressed Cl(-) extrusion function of E50_Q93del and M415V mutants, with mildly impaired function of A191V and S323P mutants. Cell surface expression levels of these KCC2 mutants were similar to wildtype KCC2. Heterologous expression of two KCC2 mutants, mimicking the patient status, produced a significantly greater intracellular Cl(-) level than with wildtype KCC2, but less than without KCC2. These data clearly demonstrated that partially disrupted neuronal Cl(-) extrusion, mediated by two types of differentially impaired KCC2 mutant in an individual, causes EIMFS.
Fulltext CFTR founder mutation causes protein trafficking defects in Chinese patients with cystic fibrosis

Leung GK, Ying D, Mak CC, Chen XY, Xu W, Yeung KS, et al.

Mol Genet Genomic Med, 2017 Jan;5(1):40-49.
PMID: 28116329 DOI: 10.1002/mgg3.258

Cystic fibrosis (CF) is a rare condition in Asians. Since 1985, only about 30 Chinese patients have been reported with molecular confirmation.
De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy

Itai T, Hamanaka K, Sasaki K, Wagner M, Kotzaeridou U, Brösse I, et al.

Hum Mutat, 2021 01;42(1):66-76.
PMID: 33131106 DOI: 10.1002/humu.24130

We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole-exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense-mediated mRNA decay (NMD), and one canonical splice site variant, c.272-1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272-1G>C, were clustered within 20 amino acid residues of the C-terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE.
Fulltext Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Himmelreich N, Bertoldi M, Alfadhel M, Alghamdi MA, Anikster Y, Bao X, et al.

Mol Genet Metab, 2023 Jul;139(3):107624.
PMID: 37348148 DOI: 10.1016/j.ymgme.2023.107624

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.
Corrigendum to: Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Himmelreich N, Bertoldi M, Alfadhel M, Alghamdi MA, Anikster Y, Bao X, et al.

Mol Genet Metab, 2023 Aug;139(4):107647.
PMID: 37453860 DOI: 10.1016/j.ymgme.2023.107647
Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients

Sekiguchi F, Tsurusaki Y, Okamoto N, Teik KW, Mizuno S, Suzumura H, et al.

J Hum Genet, 2019 Dec;64(12):1173-1186.
PMID: 31530938 DOI: 10.1038/s10038-019-0667-4

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
Oncologist-led BRCA counselling improves access to cancer genetic testing in middle-income Asian country, with no significant impact on psychosocial outcomes

Yoon SY, Wong SW, Lim J, Ahmad S, Mariapun S, Padmanabhan H, et al.

J Med Genet, 2022 Mar;59(3):220-229.
PMID: 33526602 DOI: 10.1136/jmedgenet-2020-107416

BACKGROUND: Identifying patients with BRCA mutations is clinically important to inform on the potential response to treatment and for risk management of patients and their relatives. However, traditional referral routes may not meet clinical needs, and therefore, mainstreaming cancer genetics has been shown to be effective in some high-income and high health-literacy settings. To date, no study has reported on the feasibility of mainstreaming in low-income and middle-income settings, where the service considerations and health literacy could detrimentally affect the feasibility of mainstreaming.
METHODS: The Mainstreaming Genetic Counselling for Ovarian Cancer Patients (MaGiC) study is a prospective, two-arm observational study comparing oncologist-led and genetics-led counselling. This study included 790 multiethnic patients with ovarian cancer from 23 sites in Malaysia. We compared the impact of different method of delivery of genetic counselling on the uptake of genetic testing and assessed the feasibility, knowledge and satisfaction of patients with ovarian cancer.
RESULTS: Oncologists were satisfied with the mainstreaming experience, with 95% indicating a desire to incorporate testing into their clinical practice. The uptake of genetic testing was similar in the mainstreaming and genetics arm (80% and 79%, respectively). Patient satisfaction was high, whereas decision conflict and psychological impact were low in both arms of the study. Notably, decisional conflict, although lower than threshold, was higher for the mainstreaming group compared with the genetics arm. Overall, 13.5% of patients had a pathogenic variant in BRCA1 or BRCA2, and there was no difference between psychosocial measures for carriers in both arms.
CONCLUSION: The MaGiC study demonstrates that mainstreaming cancer genetics is feasible in low-resource and middle-resource Asian setting and increased coverage for genetic testing.