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Mullegama-Klein-Martinez syndrome (MKMS) is a rare X-linked cohesinopathy caused by heterozygous loss-of-function variants in the STAG2 gene. Two unrelated female probands with de novo STAG2 LoF variants—a frameshift c.3458_3459del (p.Arg1033ThrfsTer22) (PMID:35887945) and a splice-site c.1196+4_1196+7del (PMID:40456439)—presented with severe intellectual disability, microcephaly, short stature, and central diabetes insipidus, confirming a consistent phenotype across cases.
STAG2 escapes X-inactivation, indicating a dosage-sensitive haploinsufficiency mechanism for LoF alleles. Clinical exome sequencing is therefore recommended for female patients with syndromic developmental delay and endocrine anomalies to enable early diagnosis and management. Key take-home: De novo STAG2 LoF variants should be considered in females with MKMS phenotypes for precise genetic counseling.
Gene–Disease AssociationLimitedTwo unrelated probands with de novo LoF variants and consistent phenotype Genetic EvidenceLimitedTwo de novo STAG2 loss-of-function variants in unrelated female cases with MKMS, no segregation Functional EvidenceLimitedEvidence of STAG2 escape from X-inactivation supports a haploinsufficiency mechanism |