10q26.1 Microdeletion: Redefining the critical regions for microcephaly and genital anomalies

Abstract

Distal 10q deletion syndrome is a well-characterized chromosomal disorder consisting of neurodevelopmental impairment, facial dysmorphism, cardiac malformations, genital and urinary tract defects, as well as digital anomalies. Patients with interstitial deletions involving band 10q26.1 present a phenotype similar to the ones with the distal 10q deletion syndrome, which led to the definition of a causal 600 kb smallest region of overlap (SRO). In this report, we describe a male patient with an interstitial 4.5 Mb deletion involving exclusively the 10q26.1 segment. He had growth and psychomotor retardation, microcephaly, flat feet, micropenis, and cryptorchidism. The patient's deleted region does not overlap the 10q SRO. We reviewed the clinical phenotype of patients with similar deletions and suggest the presence of two new SROs, one associated with microcephaly, growth and psychomotor retardation, and the other associated to genital anomalies. Interestingly, we narrowed those regions to segments encompassing five and two genes, respectively. FGFR2, NSMCE4A, and ATE1 were suggested as candidates for facial dysmorphism, growth cessation, and heart defects, respectively. WDR11 was linked to idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Its haploinsufficiency could play a crucial role in the genital anomalies of these patients.

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

“…Additional clinical features present in this patient included growth and psychomotor retardation, microcephaly and flat feet, in keeping with a contiguous gene syndrome (173).…”

“…The differences between these two murine models may be linked either to more or less thorough found to be disease-related (173). Interestingly, the male proband had micropenis and cryptorchidism (compatible with CHH), yet gonadotropin deficiency was not mentioned in this report.…”

“…CGH array-based studies have effectively been employed for KS gene discovery in a family with SEMA3A deletions that co-segregate with the KS phenotype -and which had not previously been detected by Sanger sequencing (Young Sema3A and Young unpublished results). CGH array can also detect deletions of previously known genes in patients with isolated KS or a contiguous gene syndrome (75,76,159,173,187).…”

WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome

“…There was no disruption of neighboring genes Emx2 and Fgfr2 (Appendix Fig. S1B) that are also located within the 10q26 deletion syndrome region and known to be important in forebrain and genitalia development 15,16 .…”

“…A splice-site mutation in WDR11 has also been found in a combined pituitary hormone deficiency disorder 14 . WDR11 is located within the 600kb minimal microdeletion region associated with the 10q26 deletion syndrome (MIM 609625) 15,16 . WDR11 contains twelve WD domains -minimally conserved motifs of approximately 40 amino acids forming two beta propellers potentially serving as molecular scaffolds 13 .…”