118 e-Letters

  • Novel biallelic truncating mutation in KLHL7 causing recessive Bohring-Opitz syndrome with central apnea

    We read with interest the case series of 6 patients with Bohring-Opitz syndrome (BOS) phenotype who were found to have autosomal recessive truncating mutations in the KLHL7 gene[1]. The purpose of this letter is to report a novel truncating mutation in KLHL7, and to expand the phenotype of recessive KLHL7 variants.
    Our patient is a now 32-month-old male of Guatemalan descent who was born at 37 weeks’ gestation after a pregnancy complicated by fetal hydronephrosis, IUGR, and maternal hypertension. Birthweight was 2.5 kg, and he failed the neonatal hearing screen bilaterally. He was admitted to the NICU for desaturation events and was treated with supplemental oxygen. Polysomnography was performed at 4 weeks of life and identified central sleep apnea, with a central apnea index of 11 events/hour and no significant obstructive component. PHOX2B testing ruled out congenital central hypoventilation syndrome. A brain MRI demonstrated hypoplasia of the corpus callosum, delayed myelination, pontine hypoplasia, and subependymal nodular heterotopia along the lateral ventricles. A chromosome microarray was negative for deletions and duplications, though it indicated multiple areas of homozygosity (combined total length ~24 Mb).
    He demonstrated some neck control at 3 months of age, and at age 2 years was able to roll for mobility. He remains nonverbal, tracheosteomy- and gastrostomy tube-dependent. Kyphoscoliosis was noted at 11 months of age and is progressing. He is also...

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  • Milder phenotype in a boy with Bainbridge Ropers Syndrome and ASXL3 mutation. Expanding the phenotypic spectrum

    We read with interest the case series of 12 patients with loss-of-function denovo heterozygous mutations in ASXL3, reported by Balasubramanian et al in August 2017. We want to report on a further case of Bainbridge – Ropers Syndrome (BRS) seen in our department. The purpose of this letter is two-fold. The first is to report on the mild features of BRS and the second is to expand the spectrum of features in BRS reiterating that all cases may not have severe features.

    The proband is now 7 years old who first presented to the genetic services at the age of 3 years with global developmental delay and epilepsy. He is the first child of non-consanguineous healthy parent of Indian heritage. There is no family history of learning difficulties, autism or developmental delay.

    He was born after a normal pregnancy by LSCS for prolonged labour with a birth weight of 2.9kg at term. He started sitting independently at 16 months and walking at 22 months. He has speech and language delay. He initially presented with 2 episodes of febrile convulsions; the first lasting 1 minute and second 10 minutes, at 3 and a half years of age. He then went on to develop tonic- clonic seizures thereafter all requiring hospital admission. He was recruited to the deciphering development disorder project (DDD) and on whole exome sequencing detected two variants in ASXL3 and DMD gene respectively.

    This variant is predicted to cause a frameshift mutation resulting in a premature terminat...

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  • Response

    We thank our colleagues for their interest in our study recently published in the Journal of Medical Genetics entitled ‘Risk assessment of maternally inherited SDHD paraganglioma and pheochromocytoma’.
    In response, we would like to underline that our study is a prospective study (see 'Methods' section) and not a case study.
    Today, the French national registry for hereditary paraganglioma (PGL.R) contains 193 SDHD different families carrying more than 60 different mutations, which is different from the Dutch situation where 87.1% of the SDHD-mutation carriers have the same founder Dutch mutation p.Asp92Tyr [1]. As explained in our paper, we have launched this prospective study because of the few cases of SDHD-tumors inherited via the maternal line reported in the literature, but also because we were aware of three other putative cases among patients suffering from paraganglioma or pheochromocytoma (PPGL) registered in PGL.R. Unfortunately, for those three cases we were not able to collect tumor tissues to definitely prove the role of the maternally inherited SDHD mutation in the tumorigenesis. The identification of a new case, a young asymptomatic woman, by our prospective study was nevertheless a surprise for us. So we strongly suggest our colleagues to take advantage from their large cohort of 600 at-risk subjects to perform the same prospective study in asymptomatic subjects, although most of them would carry the same SDHD founder mutation, to confi...

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  • Should we screen carriers of maternally inherited SDHD mutations?
    Jean-Pierre Bayley

    Dear Editor,

    We are writing to comment on a recent paper published in your journal by Burnichon and colleagues: Burnichon N, et al. Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med Genet. 2017; 54:125-133.

    In this paper a case study is presented describing development of pheochromocytoma in a carrier of an SDHD mutation. Although at first sight not an uncommon occu...

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  • Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)

    Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)

    Boersma, H.J.1, M.V. Heitink2, J.M. van de Kamp3, van Geel, M 1,4

    1 Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
    2 Department of Dermatology, VieCuri, Venlo, The Netherlands
    3 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
    4 Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands

    With great interest, we read the article by Balboa-Beltran et al [1], where they presented a three-generation family with a phenotype of typical Milroy disease without mutations in FLT4 but instead in VEGFC. Milroy disease is an autosomal dominant, congenital form of primary lymphoedema with reduced penetrance. In approximately 70% of Milroy disease patients, mutations in FLT4 are identified [2]. Connell et al. presented research wherein FLT4 pathogenic variants were detected in 75% of clearly affected patients having a positive family history and in 68% of typical Milroy patients but without a family history [3], suggesting that other genes may be involved. Balboa-Beltran et al [1], detected a novel nonsense mutation (p.(Arg210*)) in VEGFC by exome sequencing causing Milroy-like disease. They found that all carriers of this VEGFC mutation exhibited the clinical diagnostic criteria of Milroy disease, inclu...

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  • Could a mutation in the hair keratin KRT83 cause recessive progressive symmetric erythrokeratoderma?
    Yuval Ramot

    Yuval Ramot1, Abraham Zlotogorski1, Maurice van Steensel2,3,4

    1 Department of Dermatology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel

    2 School of Medicine and School of Life Sciences, University of Dundee, United Kingdom

    3 Institute of Medical Biology, Singapore

    4 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

    In their rec...

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  • Re:NONO mutations and non compaction cardiomyopathy
    Daryl Armstrong Scott

    We only became aware of the paper by Reinstein et al. after our manuscript was published online. It is gratifying to know that we are not the only group who has identified left ventricular non-compaction (LVNC) in males with loss-of-function mutations in NONO.

    Conflict of Interest:

    None declared

  • NONO mutations and non compaction cardiomyopathy
    Eyal Reinstein

    The association has been described before but is not cited in the JMG manuscript

    Eur J Hum Genet. 2016 Jun 22. doi: 10.1038/ejhg.2016.72.

    Intellectual disability and non-compaction cardiomyopathy with a de novo NONO mutation identified by exome sequencing.

    Conflict of Interest:

    None declared

  • Re:A p.R464 H variation in the CCDC88C gene may not cause a dominant form of spinocerebellar ataxia
    Edwin Ho-Yin Chan

    To the Editor of Journal of Medical Genetics:

    Enabled by recent advances in sequencing technologies, genotypes from thousands of individuals are now available in online databases. While most of them aim to be the reference source of genotypes from healthy individuals, however, due to the lack of accompanying clinical data, geneticists now face the challenge of separating pathogenic mutations and rare polymorphisms. The fr...

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  • A p.R464 H variation in the CCDC88C gene may not cause a dominant form of spinocerebellar ataxia
    Yoshihisa Takiyama

    To the editor:

    The report that a novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia that appeared in your Journal (1) is of great interest. Although we identified the same heterozygous missense variation (c.1391G>A, p.R464H) as that reported (1) in a Japanese patient with autosomal dominant cerebellar ataxia (ADCA), we report here that this varia...

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