Table 2 Summarized clinical features, presented with HPO (Human Phenotype Ontology) nomenclature, of all individuals with a CLCN4-related neurodevelopmental condition from this study and from previous reports (in the case that detailed clinical data were available).

From: Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

 

Feature

HPO term

Males

Females

 

Males and females total

   

All variants

De novo variants

Inherited or inheritance unknown variants

All variants

All variants

   

Previously reported positive informative/total informative

This study positive informative/total informative

Total positive/ total informative

Previously reported positive informative/total informative

This study positive informative/total informative

Total positive/ total informative

Previously reported positive informative/total informative

This study positive informative/total informative

Total positive/ total informative

Total positive/ total informative

Total positive/ total informative

 

Unaffected

HP:0032321

0/36 (0%)

0/22 (0%)

0/58 (0%)

0/5 (0%)

2/15 (13.3%)

2/20 (10%)

22/25 (88%)

13/19 (68.4%)

35/44 (79.5%)

37/64 (57.8%)

37/122 (30.3%)

Neurodevelopment

Borderline intellectual disability

HP:0006889

1/36 (2.8%)

0/22 (0%)

1/58 (1.7%)

1/5 (20%)

0/15 (0%)

1/20 (5%)

0/25 (0%)

0/19 (0%)

0/44 (0%)

1/64 (1.6%)

2/122 (1.6%)

 

Mild intellectual disability

HP:0001256

9/36 (25%)

4/22 (18.2%)

13/58 (22.4%)

0/5 (0%)

6/15 (40%)

6/20 (30%)

1/25 (4%)

5/19 (26.3%)

6/44 (13.6%)

12/64 (18.8%)

25/122 (20.5%)

 

Moderate intellectual disability

HP:0002342

9/36 (25%)

9/22 (41%)

18/58 (31%)

2/5 (40%)

5/15(33.3%)

7/20 (35%)

0/25 (0%)

1/19* (5.3%)

1/44 (2.3%)

8/64 (12.5%)

26/122 (21.3%)

 

Severe/profound intellectual disability

HP:0010864

17/36 (47.2%)

7/22 (31.8%)

24/58 (41.4%)

2/5 (40%)

2/15 (13.3%)

4/20 (20%)

2/25 (8%)

0/19 (0%)

2/44 (4.5%)

6/64 (9.4%)

30/122 (24.6%)

 

Specific learning disability

HP:0001328

0/36 (0%)

2/22 (9.1%)

2/58 (3.4%)

0/5 (0%)

1/15 (6.7%)

1/20 (5%)

0/25 (0%)

0/19 (0%)

0/44 (0%)

1/64 (1.6%)

3/122 (2.5%)

 

Delayed speech and language

HP:0000750

36/36 (100%)

22/22 (100%)

58/58 (100%)

5/5 (100%)

14/15 (93.3%)

19/20 (95%)

NA

6/19 (31.6%)

6/44 (13.6%)

25/64 (39%)

83/122 (68%)

Neurology

Epilepsy

HP:0001250

22/36 (61.1%)

13/22 (59.1%)*

35/58 (60.3%)

2/5 (40%)

3/15* (20%)

5/20 (25%)

1/25 (4%)

1/19 (5.3%)

2/44 (4.5%)

7/64 (10.9%)

42/122 (34.4%)

 

Well-controlled epilepsy

NA

8/22 (36.4%)

10/13 (77%)

18/35 (51.4%)

1/2 (50%)

3/3 (100%)

4/5 (80%)

0/1 (0%)

1/1 (100%)

1/2 (50%)

5/7 (71.4%)

23/42 (54.8%)

 

Treatment-resistant epilepsy

NA

12/22 (54.5%)

3/13 (23.1%)

15/35 (42.9%)

1/2 (50%)

0/3 (0%)

1/5 (20%)

1/1 (100%)

0/1 (0%)

1/2 (50%)

2/7 (28.6%)

17/42 (40.5%)

 

Information about seizure control not available

NA

2/22 (9.1%)

0/13 (0%)

2/35 (5.7%)

0/2 (0%)

0/3 (0%)

0/5 (0%)

0/1 (0%)

0/1 (0%)

0/2 (0%)

0/7 (0%)

2/42 (4.8%)

 

Infantile hypotonia/ neonatal hypotonia

HP:0001252

11/36 (31%)

12/22 (54.5%)

23/58 (39.6%)

3/5 (60%)

8/15 (53.3%)

11/20 (55%)

1/18 (5.6%)

2/19 (10.5%)

3/37 (8.1%)

14/57 (24.6%)

37/115 (32.2%)

 

Progressive neurological manifestations

HP:0001251; HP:0002191; HP:0001252; HP:0004305; ORPHA:279882

8/36 (22.2%)

7/22 (31.8%)

15/58 (25.9%)

1/5 (20%)

6/15 (40%)

7/20 (35%)

2/18 (11.1%)

1/19 (5.3%)

3/37 (8.1%)

10/57 (17.5%)

25/115 (21.7%)

 

Abnormality of the brain

HP:0002363

14/18 (77.8%)

10/17 (58.8%)

24/35 (68.6%)

2/4 (50%)

8/13 (61.5%)

10/17 (58.8%)

1/1 (100%)

2/2 (100%)

3/3 (100%)

13/20 (65%)

37/55 (67.3%)

 

Abnormality of white matter (e.g., white matter hyperintensities/ periventricular leukomalacia/ delayed or abnormal myelination)

HP:0002500

11/18 (61.1%)

9/17 (52.9%)

20/35 (57.1%)

2/4 (50%)

3/13 (23.1%)

5/17 (29.4%)

1/1 (100%)

0/2 (0%)

1/3 (33.3%)

6/20 (30%)

26/55 (47.3%)

 

Abnormality of the corpus callosum

HP:0001273

6/18 (33%)

8/17 (47%)

14/35 (40%)

1/4 (25%)

3/13 (23.1%)

4/17 (23.5%)

1/1 (100%)

0/2 (0%)

1/3 (33.3%)

5/20 (25%)

19/55 (34.5%)

 

Cerebral and/ or cerebellar atrophy

HP:0002059; HP:0007360

6/18 (33%)

2/17 (11.8%)

8/35 (22.8%)

2/4 (50%)

5/13 (38.5%)

7/17 (41.2%)

1/1 (100%)

0/2 (0%)

1/3 (33.3%)

8/20 (40%)

16/55 (29.1%)

 

Other abnormality of the brain, e.g., Cortical dysplasia/ sclerosis/ cortical hyperintensities

HP:0002539

1/18 (5.5%)

1/17 (5.9%)

2/35 (5.7%)

1/4 (25%)

3/13 (23.1%)

4/17 (23.5%)

0/1 (0%)

2/2 (100%)

2/3 (66.7%)

6/20 (30%)

8/55 (14.5%)

Psychiatry

Autism spectrum disorder or autistic behavior

HP:0000729

2/36 (5.5%)

12/22 (54.5%)

14/58 (24.1%)

0/5 (0%)

6/15 (40%)

6/20 (30%)

1/18 (5.5%)

4/19 (21%)

5/37 (13.5%)

11/57 (19.3%)

25/115 (21.7%)

 

Depression/ bipolar disorder

HP:0000716

4/36 (11.1%)

1/22 (4.5%)

5/58 (8.6%)

0/5 (0%)

1/15 (6.7%)

1/20 (5%)

1/18 (5.5%)

2/19 (10.5%)

3/37 (8.1%)

4/57 (7%)

9/115 (7.8%)

 

Anxiety

HP:0000739

4/36 (11.1%)

6/22 (27.3%)

10/58 (17.2%)

1/5 (20%)

8/15 (53.3%)

9/20 (45%)

1/18 (5.5%)

2/19 (10.5%)

3/37 (8.1%)

12/57 (21.1%)

22/115 (19.1%)

 

Obsessive and or compulsive behaviors

HP:0000722

2/36 (5.6%)

4/22 (18.2%)

6/58 (10.3%)

0/5 (0%)

2/15 (13.3%)

2/20 (10%)

0/18 (0%)

1/19 (5.3%)

1/37 (2.7%)

3/57 (5.3%)

9/115 (7.8%)

 

Attention Deficit Hyperactivity Disorder/ or significant hyperactivity/ restlessness/ impulsivity

HP:0007018

4/36 (11.1%)

13/22 (59.1%)

17/58 (29.3%)

0/5 (0%)

7/15 (46.7%)

7/20 (35%)

0/18 (0%)

3/19 (15.8%)

3/37 (8.1%)

10/57 (17.5%)

27/115 (23.5%)

 

Psychotic disorder

HP:0000709

0/36 (0%)

1/22 (4.5%)

1/58 (1.7%)

0/5 (0%)

0/15 (0%)

0/20 (0%)

0/18 (0%)

0/19 (0%)

0/37 (0%)

0/57 (0%)

2/115 (1.7%)

 

Anger outbursts/ aggressive behavior

HP:0000718

8/36 (22.2%)

8/22 (36.4%)

16/58 (27.6%)

2/5 (40%)

4/15 (26.7%)

6/20 (30%)

0/18 (0%)

1/19 (5.3%)

1/37 (2.7%)

7/57 (12.3%)

23/115 (20%)

Gastrointestinal and growth

Gastroesophageal reflux

HP:0002020

1/36* (2.8%)

8/22 (36.4%)

9/58 (15.5%)

0/5 (0%)

5/15 (33.3%)

5/20 (25%)

0/18 (0%)

1/19 (5.3%)

1/37 (2.7%)

6/57 (10.5%)

15/115 (13%)

 

Constipation

HP:0002019

0/36 (0%)

8/22 (36.4%)

8/58 (13.8%)

1/5 (20%)

6/15 (40%)

7/20 (35%)

0/18 (0%)

1/19 (5.3%)

1/37 (2.7%)

8/57 (14%)

16/115 (13.9%)

 

Feeding difficulties

HP:0011968

2/36 (5.6%)

8/22 (36.4%)

10/58 (17.2%)

3/5 (60%)

8/15 (53.3%)

11/20 (55%)

0/18 (0%)

3/19 (15.8%)

3/37 (8.1%)

14/57 (24.6%)

24/115 (20.9%)

 

Secondary microcephaly

HP:0005484

5/28 (17.8%)

4/20 (20%)

9/48 (18.7%)

2/5 (40%)

9/11 (81.8%)

11/16 (68.7%)

0/18 (0%)

1/19 (5.3%)

1/37 (2.7%)

12/53 (22.6%)

21/115 (18.3%)

 

Failure to thrive

HP:0001508

2/27 (7.4%)

4/18 (22.2%)

6/45 (13.3%)

0/5 (0%)

5/13 (38.5%)

5/18 (27.8%)

0/18 (0%)

1/19 (5.3%)

1/37 (2.7%)

6/55 (10.9%)

12/100 (12%)

 

Short stature

HP:0004322

1/27 (3.7%)

6/22 (27.2%)

7/49 (14.2%)

1/4 (20%)

4/13 (30.7%)

5/17 (29.4%)

0/18 (0%)

1/19 (5.3%)

1/37 (2.7%)

6/54 (11.1%)

13/103 (12.6%)

Other

Sleep disturbance

HP:0002360

0/36 (0%)

2/22 (9.1%)

2/58 (3.4%)

1/5 (20%)

3/13 (23.1%)

4/18 (22.2%)

0/18 (0%)

1/19 (5.3%)

1/37 (2.7%)

5/55 (9.1%)

7/113 (6.2%)

 

Scoliosis/ kyphosis

HP: 0010674

3/36 (8.3%)

1/22 (4.5%)

4/58 (6.9%)

1/5 (20%)

0/13 (0%)

1/18 (5.6%)

0/18(0%)

0/19 (0%)

0/37 (0%)

1/55 (1.8%)

5/113 (4.4%)

 

Other skeletal/ joint abnormalities

HP:0001763; HP:0030084; HP:0002829; HP:0001382; HP:0003298

1/36 (2.8%)

7/22 (31.8%)

8/58 (13.8%)

2/5 (40%)

1/13 (7.7%)

3/18 (16.7%)

0/18 (0%)

0/19 (0%)

0/37 (0%)

3/55 (5.5%)

11/113 (9.7%)

 

Hearing impairment

HP:0000403; HP:0000407

0/36 (0%)

6/22 (27.3%)

6/58 (10.3%)

0/5 (0%)

2/15 (13.3%)

2/18 (11.1%)

0/18 (0%)

1/19 (5.3%)

0/37 (0%)

2/55 (3.6%)

8/113 (7.1%)

 

Vision Impairment

HP:0000486; HP:0008058; HP:0000545; HP:0000505

0/36 (0%)

6/22 (27.3%)

6/58 (10.3%)

0/5 (0%)

3/18 (16.7%)

3/18 (16.7%)

0/18 (0%)

2/19 (10.5%)

0/37 (0%)

3/55 (5.5%)

9/113 (8%)

  1. This table excludes patients with rare missense variants from Group D, for whom the functional studies were similar to wild type, and patients from Group C that had a more severe phenotype due to an additional monogenic condition.
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