The 1q43q44 and 1q44 microdeletion syndromes have shown to be a somewhat recognizable phenotype with various degrees of developmental delay, short stature, characteristic facial features, microcephaly, and various midline defects, of which abnormalities (agenesis/hypogenesis) of the corpus callosum is the most typical.
However, the clinical phenotype of these microdeletions is quite variable. To explain such variability, incomplete penetrance, position effects, and multigenic factors have been proposed.
The size of the deletions and the resulting phenotype varies among patients. The 1q44 region is located at the very end of the long arm of chromosome 1, so both interstitial and terminal deletions have been described (patients with terminal deletions seem to have a more severe volume loss in the brain as compared with patients who harbor interstitial deletions). A constitutional ring 1 chromosome has also been observed in one patient with a 6 Megabases deletion of 1q43q44.
These microdeletions cause the loss of several genes such as AKT3 (of which haploinsufficiency should be relevant for the microcephalic trait but not for the agenesis of the corpus callosum), HNRNPU (of which heterozygous mutations are reportedly causing intellectual disability and seizures), C1orf199, ZBTB18 (previously known as ZNF238) and COX20 (previously known as FAM36A). For example, all 1q44 microdeletion patients with a seizure phenotype are missing a copy of HNRNPU, COX20 and C1orf199.
Interestingly, features typical of the 1q43q44 microdeletion syndrome have been observed in one patient with a heterozygous de novo mutation in the ZBTB18 gene.
As prenatal findings of these microdeletion syndromes, choroid plexus cysts and single umbilical artery visible by ultrasonography at the 22nd week of gestation have been reported.
The 1q43q44 and 1q44 microdeletion syndromes show core phenotypic signs which include developmental delay, short stature, characteristic facial features, microcephaly, and various midline defects, of which abnormalities (agenesis/hypogenesis) of the corpus callosum is the most typical.
In a three years old patient with 1q44 microdeletion of 1.8 Mb hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome has been described (HHE syndrome is characterized by childhood onset partial motor convulsions, hemiplegia, and epilepsy in sequence).
Other clinical signs and symptoms described in 1q44 syndrome includes: preaxial polydactyly, fronto-parietal simplified gyral pattern, additional midline defects causing cardiac, gastro-oesophageal and urogenital anomalies (such as bladder exstrophy, hypogenitalism, absent phallus).
Recommended testing workflow
In case of a suspicion of 1q43q44 or 1q44 microdeletion syndrome, array-CGH analysis is recommended.
Several 1q43q44 and 1q44 microdeletions have been well characterized and reported in the ClinVar database. Below references contain more detailed information and can be used to start further research.
A de novo 163 kb interstitial 1q44 microdeletion in a boy with thin corpus callosum, psychomotor delay and seizures. Selmer KK, Bryne E, Rødningen OK, Fannemel M. Eur J Med Genet. 2012 Dec;55(12):715-8. PMID: 22975012
Hemiconvulsion-hemiplegia-epilepsy syndrome with 1q44 microdeletion: causal or chance association. Gupta R, Agarwal M, Boqqula VR, Phadke RV, Phadke SR. Am J Med Genet A. 2014 Jan;164A(1):186-9. PMID: 24214579
High-resolution array CGH defines critical regions and candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients with microdeletions of 1q43q44. Ballif BC, Rosenfeld JA, Traylor R, Theisen A, Bader PI, Ladda RL, Sell SL, Steinraths M, Surti U, McGuire M, Williams S, Farrell SA, Filiano J, Schnur RE, Coffey LB, Tervo RC, Stroud T, Marble M, Netzloff M, Hanson K, Aylsworth AS, Bamforth JS, Babu D, Niyazov DM, Ravnan JB, Schultz RA, Lamb AN, Torchia BS, Bejjani BA, Shaffer LG. Hum Genet. 2012 Jan;131(1):145-56. PMID: 21800092
De novo mutations in moderate or severe intellectual disability. Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C, Patry L, Massicotte C, Ambalavanan A, Spiegelman D, Diallo O, Henrion E, Dionne-Laporte A, Fougerat A, Pshezhetsky AV, Venkateswaran S, Rouleau GA, Michaud JL. PLoS Genet. 2014 Oct 30;10(10):e1004772. PMID: 25356899
A patient with constitutional ring 1 chromosome characterized by SNP array CGH. Saliganan S, Lee J, Wei S. Clin Case Rep. 2016 Mar 21;4(4):442-8. PMID: 27099748
Pre- and Postnatal Analysis of Chromosome 1q44 Deletion in Agenesis of Corpus Callosum. Shetty M, Srikanth A, Kadandale J, Hegde S. Mol Syndromol. 2015 Oct;6(4):187-92. PMID: 26648835
A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome. de Munnik SA, García-Miñaúr S, Hoischen A, van Bon BW, Boycott KM, Schoots J, Hoefsloot LH, Knoers NV, Bongers EM, Brunner HG. Eur J Hum Genet. 2014 Jun;22(6):844-6. PMID: 24193349
Bladder exstrophy and extreme genital anomaly in a patient with pure terminal 1q deletion: expansion of phenotypic spectrum. Zaki MS, Gillessen-Kaesbach G, Vater I, Caliebe A, Siebert R, Kamel AK, Mohamed AM, Mazen I. Eur J Med Genet. 2012 Jan;55(1):43-8. PMID: 22061479
Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis. van Bon BW, Koolen DA, Borgatti R, Magee A, Garcia-Minaur S, Rooms L, Reardon W, Zollino M, Bonaglia MC, De Gregori M, Novara F, Grasso R, Ciccone R, van Duyvenvoorde HA, Aalbers AM, Guerrini R, Fazzi E, Nillesen WM, McCullough S, Kant SG, Marcelis CL, Pfundt R, de Leeuw N, Smeets D, Sistermans EA, Wit JM, Hamel BC, Brunner HG, Kooy F, Zuffardi O, de Vries BB. J Med Genet. 2008 Jun;45(6):346-54. PMID: 18178631