13 e-Letters

published between 2018 and 2021

  • 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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  • Comment on Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study

    Dear Editor,

    in their recent study Arends and colleagues demonstrate a significant 2.8-fold increased risk for the formation of neutralizing anti-drug antibodies (ADA) in male patients with Fabry disease (FD) when treated with agalsidase-beta (1.0 mg/kg every other week) compared to agalsidase-alfa (0.2 mg/kg every other week).[1] Interestingly, Rombach and colleagues and later Smid and colleagues reported no significant differences in a humoral response, when using an identical dosage of 0.2 mg/kg for both drugs. [2,3] Hence, the 5-fold higher dosage of agalsidase-beta and not the compound itself seems to be an important trigger for antibody formation. However, none of the studies determined the cross reactive immunological status, which is crucial for the risk of a humoral response. The subgroup analysis of patients with ADAs by Arends and colleagues also revealed a better biochemical response to agalsidase-beta at 1.0 mg/kg in terms of decreasing lyso-Gb3 levels.[1] The authors propose that a saturation of antibody titers due to the 5-fold higher dosage might lead to the observed effect. In this respect, we recently demonstrated that antibodies can be supersaturated and that appropriate (i.e. individually optimized) enzyme dosages can overcome ADA titers already during infusions, which may result in improved patients’ outcome.[4] However, in the same study, we also demonstrated that even in patients treated with low-dose enzyme replacement therapy ADA titers can...

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  • 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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