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. 2017 Apr;136(4):463-479.
doi: 10.1007/s00439-017-1772-0. Epub 2017 Mar 10.

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Christel Depienne  1   2   3   4   5 Caroline Nava  6   7   8 Boris Keren  6   7 Solveig Heide  7   9 Agnès Rastetter  6 Sandrine Passemard  10   11   12 Sandra Chantot-Bastaraud  13 Marie-Laure Moutard  14   15   16 Pankaj B Agrawal  17 Grace VanNoy  17 Joan M Stoler  17 David J Amor  18   19 Thierry Billette de Villemeur  12   14   15   20 Diane Doummar  14   16 Caroline Alby  21   22 Valérie Cormier-Daire  23   22 Catherine Garel  24 Pauline Marzin  7 Sophie Scheidecker  25 Anne de Saint-Martin  26   27 Edouard Hirsch  26   28 Christian Korff  29 Armand Bottani  30 Laurence Faivre  31   32 Alain Verloes  11 Christine Orzechowski  33 Lydie Burglen  12   34   35 Bruno Leheup  36 Joelle Roume  37 Joris Andrieux  38 Frenny Sheth  39 Chaitanya Datar  40 Michael J Parker  41 Laurent Pasquier  42 Sylvie Odent  42   43   44 Sophie Naudion  45 Marie-Ange Delrue  45   46 Cédric Le Caignec  47   48 Marie Vincent  47 Bertrand Isidor  47   48 Florence Renaldo  10   14 Fiona Stewart  49 Annick Toutain  50 Udo Koehler  51 Birgit Häckl  52 Celina von Stülpnagel  52 Gerhard Kluger  52   53 Rikke S Møller  54   55   8 Deb Pal  56   8 Tord Jonson  57 Maria Soller  58 Nienke E Verbeek  59 Mieke M van Haelst  59 Carolien de Kovel  59 Bobby Koeleman  59   60   8 Glen Monroe  59   60 Gijs van Haaften  59   60 DDD StudyTania Attié-Bitach  21   22 Lucile Boutaud  21   22 Delphine Héron  7   9   20 Cyril Mignot  61   62   63   64
Affiliations

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Christel Depienne et al. Hum Genet. 2017 Apr.

Abstract

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

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Conflict of interest statement

Funding

This study was financially supported by the Assistance Publique des Hôpitaux de Paris (AP-HP), PHRC (no PO81260), INSERM, Fondation Maladies Rares, Fondation de France (FdF—Engt no 15144), Agence de la Biomédecine, Agence Nationale de la Recherche (ANR Blanc CILAXCAL), and the “Investissements d’Avenir” programme ANR-10-IAIHU-06 (IHU-A-ICM). Dr Solveig Heide was supported by a master grant from the Fondation pour la Recherche Médicale (FRM). CD and CN are members of the Biopsy labex.

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

The study received approval from local ethical standards committees on human experimentation.

Informed consent

Informed written consent was obtained from each individual or their parents or legal representatives before blood sampling.

Figures

Fig. 1
Fig. 1
Significant genotype–phenotype correlations gained from comparison of clinical data of patients with microdeletions. a, b Alignment of microdeletions found in patients with (red bars) and without (blue bars) microcephaly showed that deletions including AKT3 (upper panel) were mostly associated with microcephaly and those excluding AKT3 (lower panel) were mostly associated with normal OFC (a). The minimal critical region (vertical rectangle with dashed borders) overlapped the 5′ region of AKT3. Diagrams in b show the percentages of patients with (red) or without (blue) microcephaly who had a microdeletion including (AKT3−) or excluding (AKT3+) AKT3 (upper panel), and comparison of the percentage of patients with (red) or without (blue) microcephaly who had a microdeletion encompassing only one of the three genes of interest, two genes or all three genes (lower panel, empty circles designate deleted genes, full circles are for non-deleted genes). c, d Alignment of the microdeletions found in patients with AnCC (AgCC red bars, DysCC pink bars, ThCC green bars) and patients without CC anomalies (blue bars) showed that deletions including ZBTB18 (upper panel) were mostly associated with all types of AnCC and those excluding ZBTB18 (lower panel) were mostly associated with normal CC. The minimal critical region (vertical rectangle with dashed borders) overlapped the entire coding sequence of ZBTB18. Diagrams in d show the percentages of patients with (orange) or without (blue) AnCC who had a microdeletion including (ZBTB18−) or excluding (ZBTB18+) ZBTB18 (upper panel), and comparison of the percentage of patients with (orange) or without (blue) AnCC who had a microdeletion encompassing only one of the three genes of interest, two genes or all three genes (lower panel, empty circles designate deleted genes, full circles are for non-deleted genes). e, f Alignment of the microdeletions found in patients with (red bars) and without (blue bars) epilepsy showed that deletions including HNRNPU (upper panel) were mostly associated with epilepsy and those excluding HNRNPU (lower panel) were mostly associated with no seizures. The minimal critical region (vertical rectangle with dashed borders) overlapped the entire coding sequence of HNRNPU and COX20. Diagrams in f show the percentages of patients with (red) or without (blue) epilepsy who had a microdeletion including (HNRNPU−) or excluding (HNRNPU+) HNRNPU (upper panel), and comparison of the percentage of patients with (red) or without (blue) epilepsy who had a microdeletion encompassing only one of the three genes of interest, two genes or all three genes (lower panel, empty circles designate deleted genes, full circles are for non-deleted genes)
Fig. 2
Fig. 2
Summary of intragenic microdeletions and point mutations in AKT3, ZBTB18 and HNRNPU. a A schematic representation of the AKT3 gene and protein, location of point mutations (somatic) and duplications (somatic or germline) identified in patients with brain overgrowth syndromes (upper panel) and comparison of intragenic AKT3 microdeletions and their association with microcephaly (lower panel). b A schematic representation of the ZBTB18 gene and protein and location of pathogenic point mutations identified in patients with ID and/or AnCC, including this study (upper panel) and the literature (lower panel). c A schematic representation of the HNRNPU gene and protein and location of pathogenic point mutations identified in patients with ID and epilepsy, including this study (upper panel) and the literature (lower panel)
Fig. 3
Fig. 3
Aspects of the corpus callosum (CC) on MRI in patients with ZBTB18 and HNRNPU mutations and deletions. a Normal CC in a patient with HNRNPU mutation (left) and ThCC in two patients with HNRNPU deletions (middle and right). b Partial AgCC (left and right) and short DysCC (middle) in three patients with ZBTB18 mutations. c ThCC (left) and normal CC (middle) in two patients with AKT3 + ZBTB18 deletions. Partial AgCC in a patient with a deletion encompassing AKT3 + ZBTB18 + HNRNPU (right)

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