Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature

Abstract

Background: Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46,XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46,XY DSD. Cases of 46,XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children's Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated. Results: Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.R356X, p.Q152X, and p.Q124X) and six missense (p.P334S, p.S662R, p.A421P,p.T992I, p.P542S, and p.R927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662R, and p.R927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function. Conclusion: Patients with 46,XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46,XY DSD.

Disorders of Sex Development: Classification, Review, and Impact on Fertility

“…(3) Hypospadias. Hypospadias is a relatively common abnormality in children, affecting approximately 1/150 newborn males [142], and is associated with the MAMLD1 (Xp28) and ATF3 (1p32.3) genes for 46,XY-isolated hypospadias [143]. Androgens influence the masculinization of the genital tubercle between 8 and 12 weeks of gestation, and control tubularization of the urethra from the perineum to the tip of the glans penis.…”

Disorders of Sex Development in Individuals Harbouring MAMLD1 Variants: WES and Interactome Evidence of Oligogenic Inheritance

“…The most significant phenotypic feature observed is hypospadias. Other phenotypes include cryptorchidism, micropenis, complete female external genitalia, and primary amenorrhea (14)(15)(16)(17).…”

“…To date, approximately 30 MAMLD1 sequence variations have been identified in 46,XY DSD patients and recorded in the human gene mutation database ( 14 ). Disease-causing MAMLD1 variants can carry nonsense, missense, or frameshift mutations; insertions; or deletions, and these may even include complex variants ( 14 ).…”

“…To date, approximately 30 MAMLD1 sequence variations have been identified in 46,XY DSD patients and recorded in the human gene mutation database ( 14 ). Disease-causing MAMLD1 variants can carry nonsense, missense, or frameshift mutations; insertions; or deletions, and these may even include complex variants ( 14 ). They are found to be scattered throughout the gene sequence and are not restricted to significant hotspots, owing to which the genotype-phenotype correlations remain obscure ( 14 ).…”

“…Disease-causing MAMLD1 variants can carry nonsense, missense, or frameshift mutations; insertions; or deletions, and these may even include complex variants ( 14 ). They are found to be scattered throughout the gene sequence and are not restricted to significant hotspots, owing to which the genotype-phenotype correlations remain obscure ( 14 ). Patients with 46,XY DSDs share a wide variety of phenotypic features ( 8 , 9 ).…”