17 e-Letters

published between 2017 and 2020

  • SDR9C7, KRT83, and increasing verisimilitude

    Science has been defined as a process of progressive approximation to the truth, so-called “increasing verisimilitude” [1]. The letter of Professor Fischer is illustrative in this regard.

    We previously described genetic analyses of a consanguineous Pakistani family diagnosed with “recessive progressive symmetric erythrokeratoderma” by multiple dermatologists. By autozygosity mapping and sequencing, we identified potentially pathogenic frameshift mutations in two genes located within a region of autozygosity on chr12q12-q14.1, SDR9C7 and KRT83, in perfect linkage disequilibrium in this family [2]. At that time we did not consider SDR9C7 a good candidate, and we concluded that the KRT83 frameshift was more likely to be causal.

    Our study was carried out in the early autumn of 2015, we wrote our paper in the spring of 2016, a revised version was accepted for publication in autumn, 2016, and our paper was published online in late 2016. Presumably at the same time, Shigehara et al. [3] carried out parallel studies, unambiguously identifying SDR9C7 as the gene for recessive congenital lamellar ichthyosis based on three families with different mutations. Their findings were published at nearly the same time as ours, and were subsequently confirmed by other investigators [4-6]. Obviously, none of this was known at the time of our study.

    With the 20:20 clarity of hindsight, it now seems clear that many of the clinical features in our study family are consisten...

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  • Letter to the Editor: “Biallelic variants in BRCA1 gene cause a recognizable phenotype within chromosomal instability syndromes reframed as BRCA1 deficiency”

    We appreciate the article by Chirita-Emandi at al (1).
    The authors showed the phenotype of nine patients with biallelic variants at BRCA1 gene associated with Fanconi anemia-like complementation group-S (MIM 617883). As it is a rare syndrome, the publication of articles describing the clinical characteristics and follow-up data are important to improve the knowledge and disseminate evidence-based information.
    In Chirita-Emandi’s article, one patient is first reported and eight are from previous studies. All patients had prenatal and postnatal growth failure, microcephaly, skin pigmentation lesions, facial dysmorphism and cancer family history. Eight presented mild developmental delay, and six had cancer. None presented bone marrow failure or immunodeficiency (1).
    In this letter, we would like to update the clinical case of one of these patients. In a previous article we reported a homozygous loss-of-function BRCA1 mutation in a 2.5-year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features (2). At 6 years-old, she evaluated with neurological symptoms and her skull tomography detected an expansive and infiltrative lesion in the encephalic trunk, compressing and displacing the IV ventricle and obliterating the prepontine cistern and the cerebellar angles. The lesion characteristics were suggestive of diffuse astrocytoma. Soon after a decompressive neurological surgery, this child died....

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  • KRT83 mutations are not associated with progressive symmetric erythrokeratoderma

    I recently came across this publication and was very surprised at some facts that seem inconsistent.
    Shah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
    First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
    In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
    To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but al...

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  • Response to 'Female carriers'

    Dear Mr Instone - Many thanks for your interest in our work and your comment! In our analyses we did look at ICD-10 diagnoses of atrial fibrillation/flutter, and self-reported heart problems in female carriers versus female non-carriers, but didn't see any difference in prevalence between the two groups (results in the Supplementary Data). However, as these are relatively crude measures, we cannot the exclude the possibility that there are actually higher rates of subtle cardiac dysfunction in female carriers relative to non-carriers, and further, more focussed studies might look at this. Regards, Dr William Davies

  • Female carriers

    Fascinated to see the comments about irregular heartbeats as an x-linked ichthyosis suffer myself. If you are carrying out further studies I wonder if there is any trend for female carriers having the same. My mother an x-linked ichthyosis carrier has always had an extra hearth beat that causes problems for medical exams and operations. Could it be used as an additional test for expectant mums for potential x-linked babies. A great article and thanks - Jeremy Instone

  • Renal tumours in neonates are often misdiagnosed -A major concern.

    We read with interest the extensive retrospective study on von Hippel-Lindau disease as described by the authors (1) . This original article enlightened us about the age of onset, initial tumour size, concomitant tumours, mutation type and mutation location had an effect on growth rate in VHL-related RCC.It was very interesting to note that these renal tumours larger than 4 cm grew faster than those smaller than 4 cm.
    Abdominal masses are frequent in newborn infants, two thirds being renal in origin and occasionally, a renal mass may be malignant and correspond to congenital mesoblastic nephroma, Wilms’ tumor, or fetal hamartoma(2).Birt-Hogg-Dubé (BHD) syndrome is another autosomal dominant genodermatosis characterized by increased risk of renal neoplasia and spontaneous pneumothorax (3) This syndrome is linked to mutations in the FLCN gene, which encodes folliculin and is preferentially expressed in the skin, kidney, and lung (4).In addition,renal epithelial and stromal tumors (REST) is a new concept gathering two benign mixed mesenchymal and epithelial tumors: cystic nephroma and mixed epithelial and stromal tumors [MEST] (5).Since 1998 new entities have surfaced in renal tumor classification and have been included in the WHO 2004 classification e.g new elements in the Bellini carcinoma definition.(6). Renal tumours of genetic origin may often confer diagnostic challenges. Whatever the nature of the renal mass, early intervention may save the kidney or the patient...

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  • A mini review with an original Case report: Russell-Silver Syndrome (RSS)

    Dr. Charles Allison,Dr. Taranika Sarkar,

    and Prof.Dr.Jogenananda Pramanik

    Careers Abroad Institute School of Medicine, Mandeville, Manchester, JM, WI.

    We read and applauded the insightful article on clinical presentation of Russell-Silver syndrome with detail molecular diagnostic criteria as presented by Price S M., et al.[1] The low birth weight child who is non-dysmorphic with a prominent forehead and triangular face is more likely to be diagnosed as SRS if they have fifth finger clinodactyly, which in itself is not uncommon.[1] The genetic syndromes which affects growth and intellectual disability have been studied extensively. It has been proved by numerous large scale studies that IUGR is associated with significant neurodevelopmental impairment.
    From a meta analysis conducted by AAP it was concluded that IUGR is associated with lower cognitive scores for school age children. Furthermore children with IUGR born SGA reared in poorer environment demonstrate significant lower professional attainment and income than those reared in more stimulating environment. Here I present a case of
    Russell-Silver Syndrome (RSS or SRS) which is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alterations. It is characterized by prenatal and postnatal growth retardation, relative macrocephaly, the triangular face and body asymmetry.[ 6] Its incidence varies from 1 in 30,000 to 1 in 1,00,000 people. Individuals with RSS...

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  • Reply to "Comment on: Kleinendorst et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018 Sep;55(9):578-586."

    In “Genetic obesity: next-generation sequencing results of 1230 patients with obesity'', we presented our obesity gene panel data [1]. In their e-letter, Chèvre et al. question our panel selection because certain genes were omitted. Our gene panel was designed in 2012 after an extensive search in OMIM and other databases. Diagnostic genetic laboratories have to accept that custom diagnostic gene panels have a delay in inclusion of the newest research findings: development and implementation take time and changes require extensive validation against set quality parameters. We acknowledge this limitation in our paper: “Since research in obesity genetics is rapidly progressing, recently identified obesity-associated genes, such as CPE were not included in this panel” [1]. Furthermore, the authors say that we omitted the MRAP2 gene. It is, however, clearly listed as part of the gene panel. We even describe six identified MRAP2 variants in Table S1. Chèvre et al. also criticize the inclusion of insulin receptor genes, since they are not robustly associated with obesity. They were not included as 'obesity causing genes', but as 'comorbidity genes' (Table S2 Sequence variants identified in comorbidity genes) [1]. Diabetes is a serious comorbidity of obesity and knowledge of these mutations is important, especially when aiming for future personalized treatment.

    The authors question the validity of how we determine the pathogenicity of identifi...

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  • Comment on: Kleinendorst et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018 Sep;55(9):578-586.

    To the Editor:
    We read with interest the article by Kleinendorst et al. on a next-generation sequencing-based gene panel analysis of 52 obesity-related genes in 1,230 patients with obesity [1]. This study is among the first to screen an exhaustive list of causal genes to determine the prevalence of monogenic obesity in a large series of severely obese children and adults recruited from a medical setting [2]. Genetic testing for obesity should be routinely performed in carefully selected patients, especially given the possibility of effective personalized treatments for a subset of monogenic cases [3]. We wanted to express several important concerns.
    First, the selection of these 52 genes is highly questionable. Several genes that have not been robustly associated with highly penetrant forms of obesity in the literature were included in the panel (e.g. IRS1, IRS2, IRS4, MCHR1), while 3 non-syndromic (MRAP2, KSR2, ADCY3) and 39 syndromic monogenic obesity genes were omitted [4,5].
    Second, the authors claim a ‘definitive diagnosis of a genetic obesity disorder’ in 3.9% of obese probands. This is a highly dubious conclusion considering that the authors used proprietary bioinformatics tools and did not detail how they classified variants as being pathogenic/likely pathogenic, uncertain, or likely begnin/begnin. In vitro functional characterization experiments are needed to confirm the pathogenicity of genetic variants [2].
    Third, the authors should have...

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  • Additional evidence for the c.428del variant in KIAA0586 as hypomorphic allele that is only disease causing in compound heterozygosity with strong mutations.

    Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
    1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
    2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
    3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
    4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
    5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria

    Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.

    In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...

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