Balakrishnan, Surya; Rachamadugu, Mouneesha; Das Bhowmik, Aneek; Bharadwaj, Karthik T. Author Information

Warburg micro syndrome (WARBM) is a rare, autosomal recessive, neurodevelopmental disorder characterized by microcephaly, cortical dysplasia, corpus callosum hypoplasia, congenital hypotonia leading to subsequent spastic quadriplegia, severe developmental delay and hypogenitalism. Ophthalmologic findings that may affect any ocular segment including characteristic, small, atonic pupils. WARBM is known to be caused by biallelic, pathogenic variants in at least five genes although additional genetic loci may exist. The RAB3GAP1 c.748 + 1G>A, p.Asp250CysfsTer24 founder variant has been described in families of Turkish ancestry. We report the clinical and molecular findings in three, unrelated, Turkish families with WARBM. A novel c.974-2A>G variant causing WARBM in three siblings of Turkish descent was found. Functional studies of the novel, c.2606 + 1G>A variant in patients' mRNA revealed skipping of exon 22 which results in a premature stop codon in exon 23. However, the clinical consequences of this variant are blended given that the individual also had a maternally inherited chromosome 3q29 microduplication.

Sabir, Ataf Hussaina,b; Cocca, Alessandrac; Cheung, Moirac,d; Irving, Melitad,e Author Information

Parmeggiani, Giulia; Gualandi, Francesca; Limarzi, Marco; Ferlini, Alessandra; Brotto, Davide; Martini, Alessandro; Sensi, Alberto Author Information

do Rosario, Michelle C.; Kaur, Parneet; Girisha, Katta Mohan; Bielas, Stephanie; Shukla, Anju Author Information

Primary autosomal recessive microcephaly 5 (MCPH5) is a rare neurodevelopmental disorder with a relatively high incidence in regions where consanguineous marriage is widely practiced; So far, only a few MCPH5 cases have been reported from China. Here, we report clinical and molecular characteristics of two Chinese MCPH5 patients, a 24-year-old woman proband and her brother, a 19-year-old man, from a nonconsanguineous family. Main manifestations in the proband were small head circumference, premature closure of fontanelles, impaired concentration and moderate intellectual disability. The proband's brother had similar symptoms, but he was hyperactive and had a more severe sloping forehead. Brain imaging revealed global reduction in brain size, especially in the frontal lobes bilaterally and anterior horns of lateral ventricles. Sequencing results revealed that both patients carried a novel nonsense variant p.Tyr2004* (c.6012_6013delTA) and a novel frameshift variant p.Arg2005Serfs*48 (c.6015_6016delGG) in the ASPM gene. These variants were interpreted to be pathogenic in the in-silico analysis. Our findings help to expand the mutation spectrum of ASPM and provide new opportunities for assisting the traditional clinical diagnosis on the cases with atypical characteristics.

We describe the case of a patient with a clinical and molecular diagnosis of Beckwith-Wiedemann Syndrome (BWS) and a clinical, radiologic and histologic diagnosis of colon isolated hypoganglionosis. BWS is a genetic multisystem disorder characterized by generalized and lateralized overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycemia and predisposition to embryonal tumors (Brioude et al., Nat Rev Endocrinol 1998; 14:229-249). Hypoganglionosis of the colon is a condition that clinically resembles Hirschsprung's disease and it is part of a group of numerous and heterogeneous conditions that are defined 'Variants of Hirschsprung's disease' (Friedmacher and Puri, Pediatr Surg Int 2013; 29:855-872). To the best of our knowledge, the association of BWS with Hirschsprung's disease has been observed only in one patient, an infant with hypoglycemia (Shah et al., BMJ Case Rep 2020; 13:e235121). We suppose that dysganglionosis could be rare comorbidity of BWS. We suggest to put particular attention to patients affected by BWS who develop early severe constipation taking into account the possibility to study them at radiologic and histologic levels to show the possible evidence of Hirschsprung's disease variants.