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Differences Identified Among Kabuki Syndrome Phenotypes

Miyake et al (DOI: 10.1002/ajmg.a.36072, p. 2234) characterize differences between phenotypes of Kabuki syndrome (KS) caused by MML2 and KDM6A gene mutations.

KS is a congenital syndrome marked by developmental delay, intellectual disability, and specific facial features. These include long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities.

The researchers identified 50 MLL2 and five KDM6A mutations among 81 patients with KS. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Researchers found non-protein, truncating-type MLL2 mutations mainly around functional domains, and truncating-type mutations scattered through the entire coding region.

The facial features of patients in the MLL2 truncating-type mutation group were typical of the 10 originally reported patients with Kabuki syndrome. Facial features for the other group were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than the KDM6A mutation cohort. Short stature and postnatal growth retardation were observed in all patients with KDM6A mutations, but in only half of those with MLL2 mutations, the researchers noted.

Figure 1.

Figure 3E. Hand images of patients with Kabuki syndrome show short fifth fingers and prominent digit pads (indicated by arrows).


Central apnea and obstructive apnea are possible in autosomal recessive auriculocondylar syndrome (ACS), while patients presenting with the extra-craniofacial phenotypes may have complete loss of function of PLCB4, write Kido et al (DOI: 10.1002/ajmg.a.36066, p. 2339).

ACS is a branchial arch syndrome, typically inherited in an autosomal dominant fashion. Patients with ACS display a malformation of the external ear known as question-mark ear, micrognathia, and mandibularcondyle hypoplasia.

Previous reports have identified PLCB4 mutations as the major cause of autosomal dominant ACS, with variants of the PLCB4 catalytic domain predicted to have a dominant negative effect. One patient with ACS born to related parents harbored a homozygous partial deletion of PLCB4, central apnea, and macropenis. Central apnea had not been previously reported with ACS. His parents— each with a heterozygous partial PLCB4 deletion—were phenotypically normal, suggesting autosomal recessive inheritance of ACS with complete loss of function of PLCB4 predicted in the patient.

The authors describe two brothers with ACS caused by compound heterozygous splice site mutations in PLCB4. The patients were born to the same unrelated and healthy parents. Each parent harbored one of the mutations, indicating autosomal recessive ACS. Both brothers had mixed apneas, gastrointestinal transit defects, and macropenis, in addition to typical craniofacial features of ACS.

Figure 2.

Figure 1Aiv. Patients with auriculocondylar syndrome present with micrognathia, question-mark ear (shown above), and prominent cheeks.


Obstructive sleep apnea syndrome (OSAS) may be a common comorbidity in adolescents and young adults with Down syndrome (DS) and depression, write Capone et al (DOI: 10.1002/ajmg.a.36052, p. 2188).

Adolescents and young adults with DS sometimes experience new-onset mood disorder and decline in adaptive skills. To better characterize this clinical phenomenon, the researchers investigated OSAS as a possible contribution.

Patients with DS and/or medical and mental health concerns were analyzed. When mood symptoms were present, researchers made an axis I diagnosis using DSM- IV-R criteria, while patients without an axis I diagnosis served as controls.

After examining caretaker responses to Reiss scales for children's dual diagnosis and the aberrant behavior checklist, the researchers found 28 patients meeting criteria for major depressive episode (MDE), and referred them—and nine patients without psychopathology—for overnight polysomnography.

Functional decline was reported in 68% of patients with MDE, but not in any of the patient controls. Some 86% of patients had OSAS, compared with only 44% of the patient controls, while moderate-to-severe OSAS was present in 54% of patients, compared to only 11% of the patient controls. Intermittent sleep-associated hypoxia and rapid-eye movement sleep deficits were also more frequent in the patients.

Recognition of this association between DS, OSAS, and depression may be critical to understanding the pathogenesis and management of mood-related disorders and functional decline in affected individuals, say researchers.