Identification of a new mutation in kmt2c causing Kleefstra syndrome TYPE 2: A very rare disorder characterized by autism and development delay
Antonella Peduto1, MD et PhD, Eleonora Barabesi2, MD, Maria Chiara Giraudo2, MD, Franco Fioretto2, MD, Davide Colavito3, MS, Alberta Leon3, MS, Lorena Sorasio1, MD
1Pediatric Unit, S. Croce and Carle Hospital, Via M. Coppino 26, Cuneo, Italy.
2Child Neuropsychiatrist, Maternal and Child Department, Child Neuropsychiatric Unit, ASL CN 1, Cuneo, Italy.
3R&I Genetics srl, C.so Stati Uniti 4. Int.F, Padova, Italy.
Antonella Peduto, MD et PhD, Pediatric Unit, S. Croce and Carle Hospital, Via M. Coppino 26, 12100 Cuneo- Italy.
Eleonora Barabesi, MD, Child Neuropsychiatrist, Maternal and Child Department, Child Neuropsychiatric Unit, ASL CN 1, Cuneo- Italy.
Figure: Patient’ brain IMR showing slight thinning
Figure 1: patient’s brain IMR showing slight thinning of the istmus between the corpus callosum and the splenius
Figure 2: patient’s brain IMR showing partial empty sella
Currently the child has making some progress in language using visual AAC (Augmentative and Alternative Communication) through photographs. Regarding motor skills, the child presents difficulties in executive control and in planning both gross and fine motor gestures. Walking still follows a wide-based pattern with feet rotated outward. He shows global hypotonia and joint laxity, difficulties in coordinating simple and complex voluntary movements. Stereotyped hand and arm movements and head shaking are observed in response to displays joy or excitement. No self/hetero-aggressiveness. Non-constant gastroesophageal reflux was reported anymore, neither food selectivity. Sleep/wake rhythm has always been regular. The child regularly undergoes medical check-ups. Logopedic and neuropsychomotor care continues with treatment cycles and rehabilitation goals periodically defined ensuing follow-up evaluations. Inclusive school practices have been initiated with a supporter teacher. Considering the neuromotor profile, the possibility of using orthotic insoles to improve gait motor organization and balance is under evaluation. Psychological support has been offered to the parents following the diagnosis, as it is known that parents of individuals with autism spectrum disorder and KS experience high levels of stress13.
Figure 3,4,5: Patient’s pictures respectively at 6 months (3), 2 years (4) and 6 years old (5). We observe widely spaced eyes, saddle nose, thick eyebrows and wide forehead, slightly hinting coarse face, more evident with age.
Table 1: Patient’s neurodevelopment scores resulted by Griffhs III scale performer at 72 months of age (6 years old). Scores from 50 to 70 are extremely below for the norm requiring specific support and therapy, from 70 to 80 they are below the norm needing to be reinforced, from 90 to 115 they are perfectly in line with age.
Considering the moderate- severe global development delay, the autistic and dysmorphic features whole exome TRIO analysis was performed, at the age of three years. NGS sequencing and data interpretation highlighted the presence of a novel heterozygous nucleotidic variant c.10420C>T in the KMT2C gene predicted to result in the premature nonsense STOP codon mutation p.Gln3474Ter. TRIO analysis showed that both parents were negative for this mutation suggesting its de novo occurrence. Accordingly to the ACMG guidelines the mutation here found was classified as likely pathogenic (class 4).
At 4 years of age, development delay and autistic features were confirmed during patient’s follow up. The PEP-3 (Psycho- Educational Profile)12 was administered to the patient. The evaluation highlighted the following adaptive/developmental delays divided by areas: verbal/preverbal cognitive skills corresponding to 1 year and 6 months, expressive language below 12 months, receptive language 1 year, fine motor skills: 1 year and 10 months, gross motor skills 1 year and 5 months, motor vision imitation 1 year and 1 months. Moreover, problematic behaviors and poor social interests were noted too.
Currently at 6 years of age, Griffiths III scale showed a globally delayed developmental profile, corresponding to a developmental quotient < 20, severely below the normal range, equivalent to an age of 47 (< 1st percentile). Neurodevelopment scores are summarized in table 1.